Cyclic derivatives as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of MCP-1 of formula (I):  
                 
 
     or pharmaceutically acceptable salt forms thereof, useful for the prevention of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma.

FIELD OF THE INVENTION

[0001] This invention relates generally to modulators of chemokinereceptor activity, pharmaceutical compositions containing the same, andmethods of using the same as agents for treatment and prevention ofinflammatory diseases, allergic and autoimmune diseases, and inparticular, asthma, rheumatoid arthritis, atherosclerosis, and multiplesclerosis.

BACKGROUND OF THE INVENTION

[0002] Chemokines are chemotactic cytokines, of molecular weight 6-15kDa, that are released by a wide variety of cells to attract andactivate, among other cell types, macrophages, T and B lymphocytes,eosinophils, basophils and neutrophils (reviewed in: Luster, New Eng. J.Med. 1998, 338, 436-445 and Rollins, Blood 1997, 90, 909-928). There aretwo major classes of chemokines, CXC and CC, depending on whether thefirst two cysteines in the amino acid sequence are separated by a singleamino acid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (−1 and −2) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

[0003] The chemokines bind to specific cell-surface receptors belongingto the family of G-protein-coupled seven-transmembrane-domain proteins(reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-la, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell 1993, 72,415-425, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. Sci. USA 1994,91, 2752-2756, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and Luster,New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1α, RANTES, MCP-1] (Power, et al., J. Biol. Chem. 1995, 270,19495-19500, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or“CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, et al.,Biochemistry 1996, 35, 3362-3367); CCR-6 (or “CKR-6” or “CC-CKR-6”)[LARC] (Baba, et al., J. Biol. Chem. 1997, 272, 14893-14898); CCR-7 (or“CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62,634-644); CCR-8 (or “CKR-8” or “CC-CKR-8”) [1-309, TARC, MIP-10](Napolitano et al., J. Immunol., 1996, 157, 2759-2763, and Bernardini,et al., Eur. J. Immunol. 1998, 28, 582-588); CCR-10 (or “CKR-10” or“CC-CKR-10”) [MCP-1, MCP-3] (Bonini, et al., DNA and Cell Biol. 1997,16, 1249-1256); and CCR-11 [MCP-1, MCP-2, and MCP-4] (Schweickert, etal., J. Biol. Chem. 2000, 275, 90550).

[0004] In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin.Biotech. 1997, 8, 741-748). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR₄, CCR₂, CCR₃, CCR₅ and CCR₈, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

[0005] The chemokines and their cognate receptors have been implicatedas being important mediators of inflammatory, infectious, andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis (reviewed in: Bharat K. Trivedi, et al, Ann. ReportsMed. Chem. 2000, 35, 191; John Saunders and Christine M. Tarby, DrugDisc. Today 1999, 4, 80; Brett A. Premack and Thomas J. Schall, NatureMedicine 1996, 2, 1174). For example, the chemokine monocytechemoattractant-1 (MCP-1) and its receptor CC Chemokine Receptor 2(CCR-2) play a pivotal role in attracting leukocytes to sites ofinflammation and in subsequently activating these cells. When thechemokine MCP-1 binds to CCR-2, it induces a rapid increase inintracellular calcium concentration, increased expression of cellularadhesion molecules, cellular degranulation, and the promotion ofleukocyte migration. Demonstration of the importance of the MCP-1/CCR-2interaction has been provided by experiments with genetically modifiedmice. MCP-1−/− mice had normal numbers of leukocytes and macrophages,but were unable to recruit monocytes into sites of inflammation afterseveral different types of immune challenge (Bao Lu, et al., J. Exp.Med. 1998, 187, 601). Likewise, CCR-2−/− mice were unable to recruitmonocytes or produce interferon-γ when challenged with various exogenousagents; moreover, the leukocytes of CCR-2 null mice did not migrate inresponse to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100,2552), thereby demonstrating the specificity of the MCP-1/CCR-2interaction. Two other groups have independently reported equivalentresults with different strains of CCR-2−/− mice (William A. Kuziel, etal., Proc. Natl. Acad. Sci. USA 1997, 94, 12053, and Takao Kurihara, etal., J. Exp. Med. 1997, 186, 1757). The viability and generally normalhealth of the MCP-1−/− and CCR-2−/− animals is noteworthy, in thatdisruption of the MCP-1/CCR-2 interaction does not induce physiologicalcrisis. Taken together, these data lead one to the conclusion thatmolecules that block the actions of MCP-1 would be useful in treating anumber of inflammatory and autoimmune disorders. This hypothesis has nowbeen validated in a number of different animal disease models, asdescribed below.

[0006] Several studies have demonstrated the potential therapeutic valueof antagonism of the MCP-1/CCR₂ interaction in treating rheumatoidarthritis. A DNA vaccine encoding MCP-1 was shown recently to amelioratechronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al.,J. Clin. Invest. 2000, 106, 361). Likewise, inflammatory diseasesymptoms could be controlled via direct administration of antibodies forMCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al., J.Pathol. 1997, 182, 106), or streptococcal cell wall-induced arthritis(Ralph C. Schimmer, et al., J. Immunol. 1998, 160, 1466). Perhaps mostsignificantly, a peptide antagonist of MCP-1, MCP-1(9-76), was shownboth to prevent disease onset and to reduce disease symptoms (dependingon the time of administration) in the MRL-lpr mouse model of arthritis(Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).

[0007] Three key studies have demonstrated the potential therapeuticvalue of antagonism of the MCP-1/CCR₂ interaction in treatingatherosclerosis. For example, when MCP-1−/− mice are mated with LDLreceptor-deficient mice, an 83% reduction in aortic lipid deposition wasobserved (Long Gu, et al., Mol. Cell 1998, 2, 275). Similarly, whenMCP-1 was genetically ablated from mice which already overexpressedhuman apolipoprotein B, the resulting mice were protected fromatherosclerotic lesion formation relative to the MCP-1+/+ apoB controlmice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103, 773).Likewise, when CCR-2−/− mice are crossed with apolipoprotein E mice, asignificant decrease in the incidence of atherosclerotic lesions wasobserved (Landin Boring, et al, Nature 1998, 394, 894).

[0008] Other studies have demonstrated the potential therapeutic valueof antagonism of the MCP-1/CCR-2 interaction in treating multiplesclerosis; all of these studies have been demonstrated in experimentalautoimmune encephalomyelitis (EAE), the standard animal model formultiple scelerosis. Administration of antibodies for MCP-1 to animalswith EAE significantly diminished disease relapse (K. J. Kennedy, etal., J. Neuroimmunol. 1998, 92, 98). Furthermore, two recent reportshave now shown that CCR-2−/− mice are resistant to EAE (Brian T. Fife,et al., J. Exp. Med. 2000, 192, 899; Leonid Izikson, et al., J. Exp.Med. 2000, 192, 1075).

[0009] Other studies have demonstrated the potential therapeutic valueof antagonism of the MCP-1/CCR₂ interaction in treating asthma.Sequestration of MCP-1 with a neutralizing antibody inovalbumin-challenged mice resulted in marked decrease in bronchialhyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al., J.Exp. Med. 1998, 188, 157). It proved possible to reduce allergic airwayinflammation in Schistosoma mansoni egg-challenged mice through theadministration of antibodies for MCP-1 (Nicholas W. Lukacs, et al., J.Immunol. 1997, 158, 4398). Consistent with this, MCP-1−/− mice displayeda reduced response to challenge with Schistosoma mansoni egg (Bao Lu, etal., J. Exp. Med. 1998, 187, 601).

[0010] Other studies have demonstrated the potential therapeutic valueof antagonism of the MCP-1/CCR₂ interaction in treating kidney disease.Administration of antibodies for MCP-1 in a murine model ofglomerularnephritis resulted in a marked decrease in glomerular crescentformation and deposition of type I collagen (Clare M. Lloyd, et al., J.Exp. Med. 1997, 185, 1371). In addition, MCP-1−/− mice with inducednephrotoxic serum nephritis showed significantly less tubular damagethan their MCP-1+/+ counterparts (Gregory H. Tesch, et al., J. Clin.Invest. 1999, 103, 73).

[0011] One study has demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR₂ interaction in treating systemic lupuserythematosus. Crossing of MCP-1−/− mice with MRL-FAS^(lpr) mice—thelatter of which have a fatal autoimmune disease that is analogous tohuman systemic lupus erythematosus—results mice that have less diseaseand longer survival than the wildtype MRL-FAS^(lpr) mice (Gregory H.Tesch, et al., J. Exp. Med. 1999, 190, 1813).

[0012] One study has demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR₂ interaction in treating colitis. CCR-2−/−mice were protected from the effects of dextran sodium sulfate-inducedcolitis (Pietro G. Andres, et al., J. Immunol. 2000, 164, 6303).

[0013] One study has demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR₂ interaction in treating alveolitis. Whenrats with IgA immune complex lung injury were treated intravenously withantibodies raised against rat MCP-1 (JE), the symptoms of alveolitiswere partially aleviated (Michael L. Jones, et al., J. Immunol. 1992,149, 2147).

[0014] Other studies have provided evidence that MCP-1 is overexpressedin various disease states not mentioned above. These reports providestrong correlative evidence that MCP-1 antagonists could be usefultherapeutics for such diseases. Two reports described the overexpressionof MCP-1 in the intestinal epithelial cells and bowel mucosa of patientswith inflammatory bowel disease (H. C. Reinecker, et al.,Gastroenterology 1995, 108, 40, and Michael C. Grimm, et al., J. Leukoc.Biol. 1996, 59, 804). Two reports describe the overexpression of MCP-1rats with induced brain trauma (J. S. King, et al., J. Neuroimmunol.1994, 56, 127, and Joan W. Berman, et al., J. Immunol. 1996, 156, 3017).Another study has demonstrated the overexpression of MCP-1 in rodentcardiac allografts, suggesting a role for MCP-1 in the pathogenesis oftransplant arteriosclerosis (Mary E. Russell, et al. Proc. Natl. Acad.Sci. USA 1993, 90, 6086). The overexpression of MCP-1 has been noted inthe lung endothelial cells of patients with idiopathic pulmonaryfibrosis (Harry N. Antoniades, et al., Proc. Natl. Acad. Sci. USA 1992,89, 5371). Similarly, the overexpression of MCP-1 has been noted in theskin from patients with psoriasis (M. Deleuran, et al., J. Dermatol.Sci. 1996, 13, 228, and R. Gillitzer, et al., J. Invest. Dermatol. 1993,101, 127). Finally, a recent report has shown that MCP-1 isoverexpressed in the brains and cerebrospinal fluid of patients withHIV-1-associated dementia (Alfredo Garzino-Demo, WO 99/46991).

[0015] It should also be noted that CCR-2 has been implicated as aco-receptor for some strains of HIV (B. J. Doranz, et al., Cell 1996,85, 1149). It has also been determined that the use of CCR-2 as an HIVco-receptor can be correlated with disease progression (Ruth I. Connor,et al., J. Exp. Med. 1997, 185, 621). This finding is consistent withthe recent finding that the presence of a CCR-2 mutant, CCR₂₋₆₄I, ispositively correlated with delayed onset of HIV in the human population(Michael W. Smith, et al., Science 1997, 277, 959). Although MCP-1 hasnot been implicated in these processes, it may be that MCP-1 antagoniststhat act via binding to CCR-2 may have beneficial therapeutic effects indelaying the disease progression to AIDS in HIV-infected patients.

[0016] Recently, a number of groups have described the development ofsmall molecule antagonists of MCP-1 (reviewed in: Bharat K. Trivedi, etal, Ann. Reports Med. Chem. 2000, 35, 191). Workers at Teijen andCombichem reported the use of cyclic amines (A) as MCP-1 (TatsukiShiota, et al., WO 99/25686; Tatsuki Shiota, et al., WO 00/69815) andMIP-1α (Christine Tarby and Wilna Moree, WO 00/69820) antagonists. Thesecompounds are distinguished from those of the present invention (I) bythe requirement for the central cyclic amine grouping.

[0017] A number of other groups have also described the development ofsmall molecule antagonists of the MCP-1/CCR-2 interaction. To date,indolopiperidines (Ian T. Forbes, et al., Bioorg. Med. Chem. Lett. 2000,10, 1803), spiropiperidines (Tara Mirzadegan, et al., J. Biol. Chem.2000, 275, 25562), quaternary amines (Masanori Baba, et al., Proc. Natl.Acad. Sci. 1999, 96, 5698), 2-substituted indoles (Alan Faull and JasonKettle, WO 00/46196; Andrew John Barker, et al., WO 99/07351; AndrewJohn Barker, et al., Wo 99/07678), pyrazolone derivatives (JanakKhimchand Padia, et al., U.S. Pat. No. 6,011,052, 2000), 2-substitutedbenzimidazoles (David Thomas Connor, et al., WO 98/06703),N,N-dialkylhomopiperazines (T. Shiota, et al., WO 97/44329), bicyclicpyrroles (Andrew J. Barker, et al., WO 99/40913 and Andrew J. Barker, etal., WO 99/40914), and 5-aryl pentadienamides (K. G. Carson, et al.,Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA,1999) have all been reported as MCP-1 antagonists. The foregoingreference compounds are readily distinguished structurally from thepresent invention by virtue of substantial differences in the terminalfunctionality, the attachment functionality, or the core functionality.The prior art does not disclose nor suggest the unique combination ofstructural fragments that embody in the novel compounds describedherein. Furthermore, the prior art does not disclose or suggest that thecompounds of the present invention would be antagonists of MCP-1.

[0018] It should be noted that CCR-2 is also the receptor for thechemokines MCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med.1998, 338, 436-445). Since it is presumed that the new compounds offormula (I) described herein antagonize MCP-1 by binding to the CCR-2receptor, it may be that these compounds of formula (I) are alsoeffective antagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5that are mediated by CCR-2. Accordingly, when reference is made hereinto “antagonism of MCP-1,” it is to be assumed that this is equivalent to“antagonism of chemokine stimulation of CCR-2.”

SUMMARY OF THE INVENTION

[0019] Accordingly, the present invention provides novel antagonists orpartial agonists/antagonists of MCP-1 receptor activity, orpharmaceutically acceptable salts or prodrugs thereof.

[0020] The present invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

[0021] The present invention provides a method for treating rheumatoidarthritis, multiple sclerosis, and atherosclerosis, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

[0022] The present invention provides a method for treating inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

[0023] The present invention provides novel cyclic derivatives for usein therapy.

[0024] The present invention provides the use of novel cyclicderivatives for the manufacture of a medicament for the treatment ofinflammatory diseases.

[0025] These and other features of the invention, which will becomeapparent during the following detailed description, have been achievedby the inventors' discovery that compounds of formula (I):

[0026] or stereoisomers or pharmaceutically acceptable salts thereof,wherein Z, m, n, s, R¹, R^(1a), R^(1b), R², R⁸, R⁹, R¹⁰, R^(10a), R¹¹,R¹², and R¹³ are defined below, are effective modulators of chemokineactivity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0027] [1] Thus, in a first embodiment, the present invention providesnovel compounds of formula (I):

[0028] or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

[0029] ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein thecycloalkyl group is saturated or partially unsaturated; or a heterocycleof 3 to 7 atoms wherein the heterocycle is saturated or partiallyunsaturated, the heterocycle containing a heteroatom selected from —O—,—S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the heterocycle optionallycontaining a —C(O)—; ring B being substituted with 0-2 R⁵;

[0030] Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO²—, and—SO₂NH—;

[0031] R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl,C₁₋₄ cycloalkyl, CF₃, or alternatively, R^(1a) and R^(1b) are takentogether to from ═O;

[0032] R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁶;

[0033] R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁷;

[0034] R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),(CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),(CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);

[0035] R^(4a), at each occurrence, is independently selected from H,methyl substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynylsubstituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-4 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(4e);

[0036] R^(4b), at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e),C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4e), and a (CHR)_(r)-4-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(4e);

[0037] R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR_(4d),—C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;

[0038] R^(4d), at each occurrence, is selected from methyl, CF₃, C₁₋₆alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4e);

[0039] R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j), —C(O)NR^(4h)R^(4h),—OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h), —NR^(4h)C(O)OR^(4i), and(CH₂)_(r)phenyl;

[0040] R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

[0041] R^(4h), at each occurrence, is independently selected from H,C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀carbocyclic;

[0042] R^(4i), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue;

[0043] R^(4j), at each occurrence, is selected from CF₃, C₁₋₆ alkyl,C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue;

[0044] R⁵, at each occurrence, is independently selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),(CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b),(CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),(CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂ NR^(5a)R^(5a), C₁₋₆haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(5c);

[0045] R^(5a), at each occurrence, is independently selected from H,methyl substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynylsubstituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(5e);

[0046] R^(5b), at each occurrence, is selected from C₁₋₆ alkylsubstituted with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e),C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(5e);

[0047] R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f),(CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),(CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and(CH₂)_(r)phenyl substituted with 0-3 R^(5e);

[0048] R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5e);

[0049] R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;

[0050] R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0051] R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),—C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;

[0052] R⁶, at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(5e);

[0053] R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d),(CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6a)R^(6a),(CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)OC(O)NR^(6a) (CR′R′) rR^(6d), (CR′R′) rNR^(6a)C(O)NR^(6a)(CR′R′) rR^(6d), (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR_(6f)C(O)O(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(═NR^(6f))NR_(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a), (CR′R′) rNR^(6f)S(O)₂ (CR′R′)rR^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenyl substituted with0-3 R^(6e);

[0054] alternatively, two R⁶ on adjacent atoms on R¹ may join to form acyclic acetal;

[0055] R^(6a), at each occurrence, is selected from H, methylsubstituted with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e),C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);

[0056] R^(6b), at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e),C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆ carbocyclicresidue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(6e);

[0057] R^(6d), at each occurrence, is selected from C₃₋₈ alkenylsubstituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e),methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(6e);

[0058] R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;

[0059] R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, andC₃₋₆ cycloalkyl, and phenyl;

[0060] R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d),—C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;

[0061] R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CRIR₁)_(r)R^(7b),(CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),(CR′R¹)_(r)C(O)O(CR′R¹)_(r)R^(7d), (CR′R′)_(r)OC(O)(CR′R′) rR^(7b),(CR′R′)_(r)OC(O)NR^(7a) (CR′R′) rR^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R¹)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R¹)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(7e);

[0062] alternatively, two R⁷ on adjacent atoms on R² may join to form acyclic acetal;

[0063] R^(7a), at each occurrence, is independently selected from H,methyl substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynylsubstituted with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(7e);

[0064] R^(7b), at each occurrence, is selected from C₁₋₆ alkylsubstituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e),C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclicresidue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7e);

[0065] R^(7d), at each occurrence, is selected from C₃₋₈ alkenylsubstituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e),methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5⁻⁶membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e);

[0066] R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

[0067] R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, andC₃₋₆ cycloalkyl, and phenyl;

[0068] R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),—C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

[0069] R′, at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(6e);

[0070] R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;

[0071] R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and (CH₂)—R¹;

[0072] R¹⁰ and R^(10a) are independently selected from H, and C₁₋₄alkylsubstituted with 0-1 R^(10b),

[0073] alternatively, R¹⁰ and R^(10a) can join to form a C₃₋₆cycloalkyl;

[0074] R^(10b), at each occurrence, is independently selected from —OH,—SH, NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);

[0075] R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;

[0076] R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR_(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b),(CHR)_(r)NRllaRlla, (CHR)_(r)C(O)NRllaRlla, (CHR)_(r)C(O)NRllaORlld,(CHR)_(q)NRllaC(O)Rllb, (CHR)_(q)NR_(11a)C(O)OR^(11d),(CHR)_(q)OC(O)NR^(11a)R^(11a), (CHR)_(r)C(O)OR_(11d), a (CHR)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e);

[0077] R^(11a), at each occurrence, is independently selected from H,C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e);

[0078] R^(11b), at each occurrence, is independently selected from C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(11e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e);

[0079] R^(11d), at each occurrence, is independently selected from H,methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆ carbocyclicresidue substituted with 0-3 R^(11e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(11e);

[0080] R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC_(l-5) alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;

[0081] R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0082] R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),(CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a),(CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b),(CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),(CHR)_(r)C(O)OR_(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-5 R^(12e), and a (CHR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e);

[0083] R^(12a), at each occurrence, is independently selected from H,C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a(CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(12e);

[0084] R^(12b), at each occurrence, is independently selected from C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(12e), and a (CH₂)_(r)—S-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(12e);

[0085] R^(12d), at each occurrence, is independently selected from H,methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆ carbocyclicresidue substituted with 0-3 R^(12e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(12e);

[0086] R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;

[0087] R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0088] R¹³, at each occurrence, is independently selected from methyl,C₂₋₄ alkyl substituted with 0-1 R^(13b);

[0089] R^(13b) is selected from —OH, —SH, —NR¹³CR^(13c),—C(O)NR¹³CR^(13c), and —NHC(O)R^(13c);

[0090] R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;

[0091] n is selected from 1 and 2;

[0092] m is selected from 0 and 1;

[0093] p, at each occurrence, is independently selected from 0, 1, and2;

[0094] q, at each occurrence, is independently selected from 1, 2, 3,and 4;

[0095] r, at each occurrence, is independently selected from 0, 1, 2, 3,and 4;

[0096] s, at each occurrence, is independently selected from 0 and 1;and

[0097] t, at each occurrence, is independently selected from 2, 3, and4.

[0098] [2] Thus, in a another embodiment, the present invention providesnovel compounds of formula (I):

[0099] or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

[0100] ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein thecycloalkyl group is saturated or partially unsaturated; or a heterocycleof 3 to 7 atoms wherein the heterocycle is saturated or partiallyunsaturated, the heterocycle containing a heteroatom selected from —O—,—S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the heterocycle optionallycontaining a —C(O)—; ring B being substituted with 0-2 R⁵;

[0101] Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and—SO₂NH—;

[0102] R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl,C₁₋₄ cycloalkyl, CF₃, or alternatively, R^(1a) and R^(1b) are takentogether to from ═O;

[0103] R¹ is selected from a C₆₋₄₀ aryl group substituted with 0-5 R⁶and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁶;

[0104] R² is selected from a C₆-10 aryl group substituted with 0-5 R⁷and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁷;

[0105] R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),(CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),(CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);

[0106] R^(4a), at each occurrence, is independently selected from H,methyl substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynylsubstituted with 0-3 R^(4e), and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-4 R^(4e);

[0107] R^(4b), at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e),C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R^(4e);

[0108] R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),—C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;

[0109] R^(4d), at each occurrence, is selected from methyl, CF₃, C₁₋₆alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4e);

[0110] R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j), —C(O)NR^(4h)R^(4h),—OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h), —NR^(4h)C(O)OR^(4j), and(CH₂)_(r)phenyl;

[0111] R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

[0112] R^(4h), at each occurrence, is independently selected from H,C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀carbocyclic;

[0113] R^(4i), at each-occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue;

[0114] R^(4j), at each occurrence, is selected from CF₃, C₁₋₆ alkyl,C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue;

[0115] R⁵, at each occurrence, is independently selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),(CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)rNR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b),(CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),(CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a), C₁₋₆haloalkyl, a (CRR)_(r)-C₃₋₁₀ carbocyclic residue substituted with 0-3R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(5c);

[0116] R^(5a), at each occurrence, is independently selected from H,methyl substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynylsubstituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(5e), and a (CH₂)_(r)—S-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(5e);

[0117] R^(5b), at each occurrence, is selected from C₁₋₆ alkylsubstituted with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e),C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(5e), and a (CH₂)_(r)—S-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(5e);

[0118] R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f),(CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),(CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and(CH₂)_(r)phenyl substituted with 0-3 R^(5e);

[0119] R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5e);

[0120] R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;

[0121] R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0122] R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR_(5d),—C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;

[0123] R, at each occurrence, is selected from H, C₁₋₆ alkyl substitutedwith R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(5e);

[0124] R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′) rNR^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′) r° (CR′R′) rR_(6d),(CR′R′) rSH, (CR′R′) rC(O)H, (CR′R′) rS (CR′R′) rR^(6d), (CR′R′)rC(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6a)R^(6a),(CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR_(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R″)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(═NR^(6f))NR_(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(6e); alternatively, two R⁶ onadjacent atoms on R¹ may join to form a cyclic acetal;

[0125] R^(6a), at each occurrence, is selected from H, methylsubstituted with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e),C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);

[0126] R^(6b), at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e),C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆ carbocyclicresidue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(6e);

[0127] R^(6d), at each occurrence, is selected from C₃₋₈ alkenylsubstituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e),methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)—S-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(6e);

[0128] R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;

[0129] R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, andC₃₋₆ cycloalkyl, and phenyl;

[0130] R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR_(6d),—C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;

[0131] R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O)(CR′R₁)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R₁)_(r)OC(O)(CR′R₁)_(r)R^(7b),(CR′ R′)_(r)OC(O)NR^(7a) (CR′ R′) rR^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R″)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b),(CR′R″)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CR′R₁)_(r)S(O)_(p)(CR′R₁)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(7e);

[0132] alternatively, two R⁷ on adjacent atoms on R² may join to form acyclic acetal;

[0133] R^(7a), at each occurrence, is independently selected from H,methyl substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynylsubstituted with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(7e), and a (CH₂)_(r)—S-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(7e);

[0134] R^(7b), at each occurrence, is selected from C₁₋₆ alkylsubstituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e),C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclicresidue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7e);

[0135] R^(7d), at each occurrence, is selected from C₃₋₈ alkenylsubstituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e),methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5⁻⁶membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e);

[0136] R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

[0137] R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, andC₃₋₆ cycloalkyl, and phenyl;

[0138] R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),—C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R′, at each occurrence, isselected from H, C₁₋₆ alkyl substituted with R^(6e), C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted withR^(6e);

[0139] R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;

[0140] R⁹ is selected from, H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and(CH₂)—R¹;

[0141] R¹⁰ and R^(10a) are independently selected from H, and C₁₋₄alkylsubstituted with 0-1 R^(10b), alternatively, R¹⁰ and R^(10a) can join toform a C₃₋₆ cycloalkyl;

[0142] R^(10b), at each occurrence, is independently selected from —OH,—SH, —NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);

[0143] R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;

[0144] R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b),(CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a),(CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b),(CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a),(CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-5 R^(11e), and a (CHR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e);

[0145] R^(11a), at each occurrence, is independently selected from H,C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a(CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e);

[0146] R^(11b), at each occurrence, is independently selected from C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(11e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e);

[0147] R^(11d), at each occurrence, is independently selected from H,methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆ carbocyclicresidue substituted with 0-3 R^(11e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(11e);

[0148] R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC1-5 alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;

[0149] R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, andC₃₋₆ cycloalkyl;

[0150] R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),(CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR₁₂ aR^(12a),(CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b),(CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),(CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-5 R^(12e), and a (CHR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e);

[0151] R^(12a), at each occurrence, is independently selected from H,C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a(CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(12e); R^(12b), ateach occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(12e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e); R^(12d), at each occurrence, is independently selected fromH, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆carbocyclic residue substituted with 0-3 R^(12e), and a (CH₂)_(r)-5⁻⁶membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e);

[0152] R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

[0153] R¹³, at each occurrence, is independently selected from methyl,C₂₋₄ alkyl substituted with 0-1 R^(13b);

[0154] R^(13b) is selected from —OH, —SH, —NR_(13c)R^(13c),—C(O)NR¹³CR^(13c), and —NHC(O)R^(13c);

[0155] R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;

[0156] n is selected from 1 and 2;

[0157] m is selected from 0 and 1;

[0158] p, at each occurrence, is independently selected from 0, 1, and2;

[0159] q, at each occurrence, is independently selected from 1, 2, 3,and 4;

[0160] r, at each occurrence, is independently selected from 0, 1, 2, 3,and 4;

[0161] s, at each occurrence, is independently selected from 0 and 1;and

[0162] t, at each occurrence, is independently selected from 2, 3, and4.

[0163] [3] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0164] R¹⁰ and R^(10a) are H;

[0165] m is 0;

[0166] n is 1; and

[0167] is 0.

[0168] [4] In another embodiment, the present invention provides novelcompounds of formula (I), wherein: ring B is selected from

[0169] ring B being optionally substituted with 0-1 R⁵ and R¹¹ and R¹²are H.

[0170] [5] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0171] R⁵, at each occurrence, is independently selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),(CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)NR^(5a)C(O)OR^(5d),(CRR)_(r)OC(O)NR^(5a)R^(5a), (CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),CRR(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b),(CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),(CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl;

[0172] R^(5a), at each occurrence, is independently selected from H,methyl, C₁₋₆ alkyl substituted with 0-2 R^(5e) wherein the alkyl isselected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, C₃alkenyl substituted with 0-1 R^(5e), wherein the alkenyl is selectedfrom allyl, C₃ alkynyl substituted with 0-1 R^(5e) wherein the alkynylis selected from propynyl, and a (CH₂)_(r)—C₃₋₄ carbocyclic residuesubstituted with 0-5 R^(5e), wherein the carbocyclic residue is selectedfrom cyclopropyl, and cyclobutyl;

[0173] R^(5b), at each occurrence, is selected from C₁₋₆ alkylsubstituted with 0-2 R^(5e), wherein the alkyl is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, a(CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with 0-2 R^(5e), whereinthe carbocyclic residue is selected from cyclopropyl, and cyclobutyl;and

[0174] R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), wherein the alkyl is selected frommethyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue substituted with0-3 R^(5e).

[0175] [6] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0176] R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b),(CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a),(CRR)_(r)NR^(4a)S(O)₂R^(4b);

[0177] R, at each occurrence, is independently selected from H, methyl,ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(6e);

[0178] R⁵, at each occurrence, is independently selected from H, methyl,ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(5d), (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a),(CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)OC(O)NR^(5a)R^(5a), (CH₂)rNR^(5a)C(O)OR^(5d), (CH₂) rNR^(5a)C(O)R^(5b), (CH₂) rC(O)OR^(5b),(CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl;

[0179] R^(5a), at each occurrence, is independently selected from H,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl,cyclopropyl, and cyclobutyl; and

[0180] r, at each occurrence, is selected from 0, 1, and 2.

[0181] [7] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0182] R¹ is selected from phenyl substituted with 0-2 R⁶, and a 5-10membered heteroaryl system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R⁶ wherein the heteroaryl is selectedfrom benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

[0183] R² is selected from phenyl substituted with 0-2 R⁷, and a 5-10membered heteroaryl system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R⁷ wherein the heteroaryl is selectedfrom benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

[0184] R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,i-butyl, allyl, propynyl, (CRR)_(q)OH, (CRR)_(s)SH, (CRR)_(s)OR^(4d),(CRR)_(s)SR^(4d), (CRR)_(s)NR^(4a)R^(4a), (CRR)_(q)C(O)OH,(CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),(CRR)_(s)NR^(4a)C(O)R^(4b), (CRR)_(s)OC(O)NR^(4a)R^(4a), (CRR)sNR^(4a)C(O)OR_(4d), (CRR)_(s)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b),(CRR)_(s)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),(CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b); R^(4b) isselected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, and cyclopropyl; R^(4d) is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; and

[0185] R⁸ and R⁹ are independently selected from methyl, ethyl, propyl,i-propyl, and cyclopropyl.

[0186] [8] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0187] R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)OH, (CRR)_(r)O(CRR)_(r)R^(6d),(CRR)_(r)SH, (CRR)_(r)C(O)H, (CRR)_(r)S(CRR)_(r)R^(6d), (CRR)_(r)C(O)OH,(CRR)_(r)C(O)(CRR)_(r)R^(6b), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)NR^(6f)C(O)(CRR)_(r)R^(6b), (CRR)_(r)C(O)O(CRR)_(r)R^(6d),(CRR)_(r)NR^(6a)C(O)NR^(6a)R^(6a), (CRR) rNR^(6a)C(S)NR^(6a)R^(6a),(CRR)_(r)OC(O)(CRR)_(r)R^(6b), (CRR)_(r)S(O)_(p)(CRR)_(r)R^(6b),(CRR)_(r)S(O)₂NR^(6a)R^(6a), (CRR)_(r)NR^(6f)S(O)₂(CRR)_(r)R^(6b),(CRR)_(r)NR^(6f)S(O)₂ NR^(6a)R^(6a), C₁₋₆ haloalkyl, and (CRR)_(r)phenylsubstituted with 0-3 R^(6e);

[0188] R^(6a), at each occurrence, is independently selected from H,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,cyclopropyl and phenyl;

[0189] R^(6b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl;

[0190] R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl;

[0191] R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;

[0192] R^(6f), at each occurrence, is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl;

[0193] R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, t-butyl, pentyl, hexyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl,Br, I, F, NO₂, CN, (CRR)_(r)NR^(7a)R^(7a), (CRR)_(r)OH,(CRR)_(r)O(CH)_(r)R^(7d), (CRR)_(r)SH, (CRR)_(r)C(O)H,(CRR)_(r)S(CRR)_(r)R^(7d), (CRR)_(r)C(O)OH,(CRR)_(r)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)NR^(7a)R^(7a),(CRR)_(r)NR^(7f)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)O(CRR)_(r)R^(7d),(CRR)_(r)OC(O)(CRR)_(r)R^(7b), (CRR)_(r)NR^(7a)C(O)NR^(7a)R^(7a),(CRR)_(r)NR^(7a)C(O)O(CRR)_(r)R^(7d), (CRR)_(r)S(O)_(p)(CRR)_(r)R^(7b),(CRR)_(r)S(O)₂NR^(7a)R^(7a), (CRR)_(r)NR^(7f)S(O)₂(CRR)_(r)R^(7b), C₁₋₆haloalkyl, and (CRR)_(r)phenyl substituted with 0-3 R^(7e);

[0194] R^(7a), at each occurrence, is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, prop-2-enyl,2-methyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,CH₂-cyclopropyl, and benzyl;

[0195] R^(7b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,cyclopentyl, CH₂-cyclopentyl, cyclohexyl, CH₂-cyclohexyl, CF₃,pyrrolidinyl, morpholinyl, and azetidinyl;

[0196] R^(7d), at each occurrence, is selected from methyl, CF₃, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, andcyclopropyl;

[0197] R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

[0198] R^(7f), at each occurrence, is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl; and

[0199] r is 0 or 1.

[0200] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0201] R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂, NR^(7a)R^(7a),NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, OCF₃,C(O)R^(7b), NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

[0202] [10] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

[0203] ring B is selected from

[0204] Z is —C(O)—;

[0205] R^(1a) and R^(1b) are selected from H and methyl, oralternatively, Ria and R^(1b) are taken together to form ═O;

[0206] R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶wherein the aryl group is selected from phenyl and naphthyl, and a 5-10membered heteroaryl system containing 1-4 heteroatoms selected from Nand O, substituted with 0-3 R⁶ wherein the heteroaryl system is selectedfrom furyl, indolyl, and benzotriazolyl;

[0207] R² is phenyl substituted with 0-1 R⁷;

[0208] R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,1-butyl, t-butyl, pentyl, hexyl, and (CH₂)_(r) C(O)R^(4b);

[0209] R⁶ is selected from methyl, ethyl, propyl, i-propyl, butyl, F,Cl, Br, I, NO₂, CN, O(CH₂)_(r)R^(6d), C(O)H, SR^(6d), NR^(6a)R^(6a),OC(O)R^(6b), S(O)_(p)R_(6b), (CHR′)_(r)S(O)₂NR^(6a)R^(6a), CF₃;

[0210] R^(6a) is H methyl, or ethyl;

[0211] R^(6b) is H or methyl;

[0212] R^(6d) is methyl, phenyl, CF₃, and (CH₂)-phenyl;

[0213] R⁹ is selected from H, methyl, and (CH₂)—R¹; and

[0214] r is 0 or 1.

[0215] [11] In another embodiment, the present invention provides novelcompounds of formula (I), wherein the compound is selected from:

[0216]N-[2-[[(1S,2S)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0217]N-[2-[[(1S,2S)-2-[[(2,4-Dimethylphenyl)methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0218]N-[2-[[(1S,2S)-2-[[(2,4,6-Trimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0219]N-[2-[[(1S,2S)-2-[[(4-Benzyloxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0220]N-[2-[[(1S,2S)-2-[[(2,4-Difluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0221]N-[2-[[(1S,2S)-2-[[(2-Chloro-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0222]N-[2-[[(1S,2S)-2-[[(2-Trifluoromethyl-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0223]N-[2-[[(1S,2S)-2-[[(2,4-Dichlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0224]N-[2-[[(1S,2S)-2-[[(2-Fluoro-6-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0225]N-[2-[[(1S,2S)-2-[[(2-Chloro-5-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0226]N-[2-[[(1S,2S)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0227]N-[2-[[(1S,2S)-2-[bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0228]N-[2-[[(1S,2S)-2-[(2,4-Dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0229]N-[2-[[(1S,2S)-2-[(4-Chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0230]N-[2-[[(cis)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0231]N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0232]N-[2-[[(cis)-2-[[(4-Nitrophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0233]N-[2-[[(cis)-2-[[(4-Isopropylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0234]N-[2-[[(cis)-2-[[(4-Trifluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0235]N-[2-[[(cis)-2-[[(4-Trifluoromethoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0236]N-[2-[[(cis)-2-[[(4-Phenoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0237]N-[2-[[(cis)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0238]N-[2-[[(cis)-2-[[(2-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0239]N-[2-[[(cis)-2-[[(3-Indolyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0240]N-[2-[[(cis)-2-[[1-(4-Chlorophenyl)ethyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0241]N-[2-[[(cis)-2-[Bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0242]N-[2-[[(1S,2R)-2-[(4-Chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0243]N-[2-[[(1S,2R)-2-[(4-(Methylthio)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0244]N-[2-[[(1S,2R)-2-[(4-(Methylsulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0245]N-[2-[[(1S,2R)-2-[(4-Iodobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0246]N-[2-[[(1S,2R)-2-[(4-(Aminosulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0247] N-[2-[[(1S,2R)-2-[[(4-Chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0248]N-[2-[[(1S,2R)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0249]N-[2-[[(1S,2R)-2-[[(4-Methylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0250]N-[2-[[(cis)-2-[(4-Chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0251]N-[2-[[(cis)-2-[(4-Methylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0252]N-[2-[[(cis)-2-[(4-Fluorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0253]N-[2-[[(cis)-2-[Benzoylamino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0254]N-[2-[[(cis)-2-[(4-Bromobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0255]N-[2-[[(cis)-2-[(4-Phenoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0256]N-[2-[[(cis)-2-[(4-Trifluoromethylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0257]N-[2-[[(cis)-2-[(5-Benzotriazolecarbonyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0258]N-[2-[[(cis)-2-[(4-Iodobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0259]N-[2-[[(cis)-2-[(4-Cyanobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0260]N-[2-[[(cis)-2-[(4-Trifluoromethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0261]N-[2-[[(cis)-2-[(4-Formylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0262]N-[2-[[(cis)-2-[(4-Carbomethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0263]N-[2-[[(cis)-2-[(4-Nitrobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0264]N-[2-[[(cis)-2-[(4-Aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0265]N-[2-[[(cis)-2-[(4-Methoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0266]N-[2-[[(cis)-2-[(4-Methylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0267]N-[2-[[(cis)-2-[(4-Methylsulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0268]N-[2-[[(cis)-2-[(4-Aminosulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0269]N-[2-[[(cis)-2-[(4-Isopropylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0270]N-[2-[[(cis)-2-[(4-Phenylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0271]N-[2-[[(cis)-2-[(4-(N,N-diethylsulfamoyl)benzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0272]N-[2-[[(cis)-2-[(4-Trifluoromethylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0273]N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0274]N-[2-[[(cis)-2-[[(3,4-Dimethylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0275]N-[2-[[(cis)-2-[[(4-Methylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

[0276]2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodobenzamide;

[0277]2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-chlorobenzamide;

[0278]N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-chlorobenzamide;

[0279]N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-trifluoromethoxybenzamide;

[0280] Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;

[0281]2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamidetrifluoroacetate;

[0282]4-(Aminosulfonyl)-N-((cis)-2-{[({[2-(trifluoromethyl)anilino]carbonyl}amino)acetyl]amino}cyclohexy)benzamide;

[0283]4-(Aminosulfonyl)-N-{(cis)-2-[({[(3-chlorophenyl)sulfonyl]amino}acetyl)amino]cyclohexyl}benzamide;

[0284] Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;

[0285] Methyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;

[0286] Tert-butylN-Methyl-2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino)cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;

[0287] Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;

[0288]2-(Benzylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0289]2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0290]2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0291]2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-bromobenzamide;

[0292] Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethoxy)phenylcarbamate;

[0293]2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethoxybenzamide;

[0294]2-(Allylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0295]2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0296]2-(cyclopropylmethylene)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0297]2-(butyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0298]2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0299]2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0300]2-((2-methyl-2-propyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0301]2-((aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0302]2-(acetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0303]2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide;

[0304]2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide;

[0305]2-(Trifluoroacetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide;

[0306]2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-nitrobenzamide;

[0307] Iso-propyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;

[0308] Tert butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;

[0309]2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3,5-dinitrobenzamide;

[0310]2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0311]2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0312]2-((Cyclopentylmethylenecarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0313]2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0314]2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0315]2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0316]2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0317]2-((Methylsulfonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0318]2-((Aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0319]2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0320]2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0321]2-((2-Methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0322]2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0323]2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0324]2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0325]2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0326]2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0327]2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0328]2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0329]2-((Ethylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0330]2-((Allylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0331]2-((Iso-butylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0332]2-((Cyclopentylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0333]2-((Tert-butoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0334]2-((Iso-propoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0335]2-((Ethoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0336]2-((Pyrrolidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0337]2-((Morpholinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0338]2-((Azetidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;

[0339]2-{[1-Pyrrolidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0340]2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0341]2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methoxy)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0342]1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;

[0343][2-({[5-benzyloxycarbonylamino-2-(4-methylthio-benzoylamino)cyclohexylcarbamoyl]-methyl}carbamoyl)-4-trifluoromethylphenyl]carbamicacid tert-butyl ester;

[0344]{4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;

[0345]{4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid benzyl ester;

[0346]1-(4-Methanesulfonylbenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl-4-aminocyclohexane;

[0347]1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)cyclohexane;

[0348]1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(3-methylureido)cyclohexane;

[0349]1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-aminocyclohexane;

[0350]1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-(2-propylamino)cyclohexane;

[0351]1-(4-Methylthio-benzoylamino)-2-[2-(2-Amino-5-trifluoromethyl-benzoylamino)-acetylamino]-4-aminocyclohexane;

[0352]4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)-cyclohexane;

[0353]1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-5-aminocyclohexane;

[0354]2-Amino-N-({2-[(4-methylthiophenylamino)methyl]cyclohexylcarbamoyl}-methyl)-5-(trifluoromethyl)benzamide;

[0355]2-Isopropylamino-N-{[(cis)₂-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide;

[0356]2-(3-Isopropylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide;

[0357]2-(3-Morpholinylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide;

[0358]2-Amino-N-({2-(cis)-[3-(4-methylthiophenyl)ureido]cyclohexylcarbamoyl}methyl)-5-trifluoromethylbenzamide;

[0359]{2-[({2-(Cis)-[3-(4-methanesulfonylphenyl)ureido]cyclohexylcarbamoyl}methyl)carbamoyl]-4-trifluoromethylphenyl}carbamicacid tert-butyl ester;

[0360]2-amino-N-{2-[((3S,4R)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0361]2-Amino-N-{2-[((3R,4S)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0362]2-amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0363]N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0364]N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0365]2-Amino-N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0366]2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0367]2-Amino-N-{2-[((cis)-4-{[4-ethylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0368]N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0369]N-{2-[((cis)-4-{bis[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0370]2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0371]N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0372]2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0373]2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0374]2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0375]2-(Pyrrolidinylcarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0376]2-(Methylaminocarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0377]3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0378]N-{2-[((cis)-4-{[4-aminosulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0379]N-{2-[((cis)-4-{[4-methylsulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0380]2-Amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0381]N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0382]N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0383]2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0384]2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0385]2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0386]3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;

[0387]N-{2-[((cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;

[0388]N-{[4-Dimethylamino-2-(4-methylsulfanyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate;

[0389]N-{[2-(4-Chloro-benzylamino)-4-dimethylamino-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate;

[0390]N-{[4-Dimethylamino-2-(4-methoxy-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate; and

[0391]N-{[4-Dimethylamino-2-(4-methyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate.

[0392] In another embodiment, the present invention is directed to apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of Formula(I).

[0393] In another embodiment, the present invention is directed to amethod for modulation of chemokine or chemokine receptor activitycomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of Formula (I).

[0394] In another embodiment, the present invention is directed to amethod for modulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5activity that is mediated by the CCR2 receptor comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of Formula (I).

[0395] In another embodiment, the present invention is directed to amethod for modulation of MCP-1 activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I).

[0396] In another embodiment, the present invention is directed to amethod for treating or preventing disorders, comprising administering toa patient in need thereof a therapeutically effective amount of acompound of Formula (I), said disorders being selected fromosteoarthritis, aneurism, fever, cardiovascular effects, Crohn'sdisease, congestive heart failure, autoimmune diseases, HIV-infection,HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis,transplant arteriosclerosis, physically- or chemically-induced braintrauma, inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

[0397] In another embodiment, the present invention is directed to amethod for treating or preventing disorders, of Formula (I), whereinsaid disorders being selected from psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

[0398] In another embodiment, the present invention is directed to amethod for treating or preventing disorders, of Formula (I), whereinsaid disorders being selected from alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

[0399] In another embodiment, the present invention is directed to amethod for treating or preventing disorders, of Formula (I), whereinsaid disorders being selected from asthma, multiple sclerosis,artherosclerosis, and rheumatoid arthritis.

[0400] In another embodiment, the present invention is directed to amethod for treating or preventing rheumatoid arthritis, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

[0401] In another embodiment, the present invention is directed to amethod for treating or preventing multiple sclerosis, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

[0402] In another embodiment, the present invention is directed to amethod for treating or preventing atherosclerosis, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

[0403] In another embodiment, the present invention is directed to amethod for treating or preventing asthma, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I). In another embodiment, the present invention is directedto a method for treating or preventing inflammatory diseases, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

[0404] In another embodiment, the present invention is directed to amethod for modulation of CCR2 activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I).

[0405] In another embodiment, ring B is selected from

[0406] ring B being optionally substituted with 0-1 R⁵.

[0407] In another embodiment, ring B is selected from

[0408] In another embodiment, Z is —C(O)—.

[0409] In another embodiment, R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, (CRR)_(q)OH, (CHR)_(s)SH, (CRR)_(t)OR^(4d),(CHR)_(t)SR^(4d), (CHR)_(t)NR^(4a)R^(4a), (CHR)_(q)C(O)OH,(CHR)_(r)C(O)R^(4b), (CHR)_(r)C(O)NR^(4a)R^(4a),(CHR)_(t)NR^(4a)C(O)R^(4b), (CHR)_(t)OC(O)NR^(4a)R^(4a),(CHR)_(t)NR^(4a)C(O)OR^(4d), (CHR)_(t)NR^(4a)C(O)R^(4b),(CHR)_(r)C(O)OR^(4b), (CHR)_(t)OC(O)R^(4b), (CHR)_(r)S(O)_(p) R^(4b),(CHR)_(r)S(O)₂NR^(4a)R^(4a), (CHR)_(r)NR^(4a)S(O)₂R^(4b); and

[0410] R, at each occurrence, is independently selected from H, methyl,ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(6e).

[0411] In another embodiment, R⁴ is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CRR)_(q)OH,(CRR)_(t)SH, (CRR)_(t)oR^(4d), (CRR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a),(CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a),(CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),(CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b).

[0412] R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; and

[0413] R^(4d) is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, and cyclopropyl.

[0414] In another embodiment, R⁴ is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CH₂)_(r)C(O)R^(4b).

[0415] In another embodiment, R⁵, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl,propynyl, (CH₂)_(r)OH, (CH₂)_(r)OR^(5d), (CH₂)_(r)NR^(5a)R^(5a),(CH₂)_(r)C(O)OH, (CH₂) rC(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a),(CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)OC(O)NR^(5a)R^(5a),(CH₂)_(r)NR^(5a)C(O)OR^(5d), (CH₂)_(r)NR^(5a)C(O)R^(5b),(CH₂)_(r)C(O)OR^(5b), (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)NR^(5a)S(O)₂R^(5b),and C₁₋₆ haloalkyl; and

[0416] R^(5a), at each occurrence, is independently selected from H,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl,cyclopropyl, and cyclobutyl.

[0417] In another embodiment, R⁵, at each occurrence, is independentlyselected from H, (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)R^(5b), and(CH₂)_(r)NR^(5a)C(O)OR^(5d).

[0418] In another embodiment, R¹ is selected from phenyl substitutedwith 0-2 R⁶, naphthyl substituted with 0-2 R⁶, and a 5-10 memberedheteroaryl system containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R⁶ wherein the heteroaryl is selected from indolyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

[0419] In another embodiment, R¹ is selected from a C₆₋₁₀ aryl groupsubstituted with 0-3 R⁶ wherein the aryl group is selected from phenyland naphthyl, and a 5-10 membered heteroaryl system containing 1-4heteroatoms selected from N and O, substituted with 0-3 R⁶ wherein theheteroaryl system is selected from furyl, indolyl, and benzotriazolyl.

[0420] In another embodiment, R² is selected from phenyl substitutedwith 0-2 R⁷, and a 5-10 membered heteroaryl system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R⁷ whereinthe heteroaryl is selected from benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,thiazolyl, thienyl, and tetrazolyl.

[0421] In another embodiment, R² is selected from phenyl substitutedwith 0-2 R⁷.

[0422] In another embodiment, R⁶, at each occurrence, is selected fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl,Br, I, F, NO₂, CN, (CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH,(CH₂)_(r)O(CH₂)_(r)R^(6d), (CH₂)_(r)SH, (CH₂)_(r)C(O)H,(CH₂)_(r)S(CH₂)_(r)R^(6d), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)(CH₂)_(r)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a),(CH₂)_(r)NR^(6f)C(O)(CH₂)_(r)R^(6b), (CH₂)_(r)C(O)O(CH₂)_(r)R^(6d),(CH₂)_(r)OC(O)(CH₂)_(r)R^(6b), (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(6b),(CH₂)_(r)S(O)₂NR^(6a)R^(6a), (CH₂)_(r)NR^(6f)S(O)₂(CH₂)_(r)R^(6b), (CH₂)rNR^(6f)S(O)₂ NR^(6a)R^(6a), C₁₋₆ haloalkyl, and (CH₂)_(r)phenylsubstituted with 0-3 R^(6e);

[0423] R^(6a), at each occurrence, is independently selected from H,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,cyclopropyl and phenyl;

[0424] R^(6b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl;

[0425] R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl;

[0426] R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; and

[0427] R^(6f), at each occurrence, is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl.

[0428] In another embodiment, R⁶ is selected from methyl, ethyl, propyl,i-propyl, butyl, F, Cl, Br, I, NO₂, CN, O(CH₂)_(r)R^(6d), C(O)H,SR^(6d), NR^(6a)R^(6a), OC(O)R^(6b), S(O)_(p)R^(6b),(CHR′)_(r)S(O)₂NR^(6a)R^(6a), CF₃;

[0429] R^(6a) is H, methyl, or ethyl;

[0430] R^(6b) is H or methyl; and

[0431] R^(6d) is methyl, phenyl, CF₃, and (CH₂)-phenyl.

[0432] In another embodiment, R⁷ is selected from methyl, ethyl, propyl,i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CH₂)_(r)NR^(7a)R^(7a), (CH₂)_(r)OH,(CH₂)_(r)O(CH)_(r)R^(7d), (CH₂)_(r)SH, (CH₂)_(r)C(O)H,(CH₂)_(r)S(CH₂)_(r)R^(7d), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)(CH₂)_(r)R^(7b), (CH₂)_(r)C(O)NR^(7a)R^(7a),(CH₂)_(r)NR^(7f)C(O)(CH₂)_(r)R^(7b), (CH₂)_(r)C(O)O(CH₂)_(r)R^(7d),(CH₂)_(r)OC(O)(CH₂)_(r)R^(7b), (CH₂)_(r)NR^(7a)C(O)NR^(7a)R^(7a), (CH₂)rNR^(7a)C(O)O(CH₂) rR^(7d), (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(7b),(CH₂)_(r)S(O)₂NR^(7a)R^(7a), (CH₂)_(r)NR^(7f)S(O)₂(CH₂)_(r)R^(7b), C₁₋₆haloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(7e);

[0433] R^(7a), at each occurrence, is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, andcyclopropyl;

[0434] R^(7b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, andcyclopropyl;

[0435] R^(7d), at each occurrence, is selected from methyl, CF₃, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, andcyclopropyl;

[0436] R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; and

[0437] R^(7f), at each occurrence, is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,and phenyl.

[0438] In another embodiment, R⁷ is selected from methyl, ethyl, propyl,i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂,NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d),CF₃, OCF₃, C(O)R^(7b), NR^(7f)C(O)NHR^(7a), and NHS(O)₂R^(7b).

[0439] In another embodiment, R⁸ is H.

[0440] In another embodiment, R⁹ is H, methyl, or CH₂—R¹.

[0441] In another embodiment, R¹¹ and R¹² are H.

[0442] The invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention also encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment to describe additional even more preferred embodiments of thepresent invention. Furthermore, any elements of an embodiment are meantto be combined with any and all other elements from any of theembodiments to describe additional embodiments.

[0443] Definitions

[0444] The compounds herein described may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. Many geometric isomers of olefins, C═N double bonds,and the like can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. Cisand trans geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms. All chiral, diastereomeric, racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

[0445] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

[0446] When any variable (e.g., R_(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R_(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0447] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0448] As used herein, “C₁₋₈ alkyl” is intended to include both branchedand straight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

[0449] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo, and iodo; and “haloalkyl” is intended to include both branchedand straight-chain saturated aliphatic hydrocarbon groups, for exampleCF₃, having the specified number of carbon atoms, substituted with 1 ormore halogen (for example −C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

[0450] As used herein, the term “5-6-membered cyclic ketal” is intendedto mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxaneand their derivatives.

[0451] As used herein, “carbocycle” or “carbocyclic residue” is intendedto mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of whichmay be saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

[0452] As used herein, the term “heterocycle” or “heterocyclic system”is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclicor 7, 8, 9, or 10-membered bicyclic heterocyclic ring which issaturated, partially unsaturated or unsaturated (aromatic), and whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, NH, O and S and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom which results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Ifspecifically noted, a nitrogen in the heterocycle may optionally bequaternized. It is preferred that when the total number of S and O atomsin the heterocycle exceeds 1, then these heteroatoms are not adjacent toone another. As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heterotams independentlyselected from the group consisting of N, O and S and is aromatic innature.

[0453] Examples of heterocycles include, but are not limited to,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,1H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazble, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,tetrazolyl, and xanthenyl. In another aspect of the invention, theheterocycles include, but are not limited to, pyridinyl, thiophenyl,furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl,piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fusedring and spiro compounds containing, for example, the aboveheterocycles.

[0454] Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, examples of heteroaryls are indolyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl,isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl.

[0455] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[0456] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[0457] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0458] Since prodrugs are known to enhance numerous desirable qualitiesof pharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc.) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

[0459] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

[0460] “Therapeutically effective amount” is intended to include anamount of a compound of the present invention alone or in combinationwith other active ingredients effective to inhibit MCP-1 or effective totreat or prevent inflammatory disorders.

Synthesis

[0461] The compounds of the present invention can be prepared in anumber of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below. All references cited hereinare hereby incorporated in their entirety herein by reference.

[0462] The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

[0463] A series of compounds of formulas 6 and 7 are available via themethods shown in Scheme 1. A cyclic diamine 1 can be monoprotected toprovide 2. This material can be coupled to the acid 3 to yield the amide4. Once the protecting group is removed, a reductive amination can beperformed to afford target 6. This can be alkylated again to give target7.

[0464] A series of compounds of formulas 10 and 11 are available asshown in Scheme 2. The protecting group on intermediate 4 can beremoved, and a reductive amination can be performed to yield 8. Thismaterial can be coupled to acid 9 to give target 10. A second target canbe synthesized by protecting group removal from intermediate 4 anddirect coupling of 9 to give the target 11.

[0465] A series of compounds of formulas 20 and 21 are synthesized asshown in Scheme 3. A cyclic 1,2-diamine like 12 (for example, thecommercially available 1,2-diaminocyclohexane) can be mono-protected asa Boc carbamate via BOC-ON (Brechbiel et al., Bioorg. Med. Chem. 1997,5, 1925). The amine 13 can be directly coupled with 14 to yield theamide 15. In a second pathway, or a stepwise version, 13 can be coupledto 16 as the first step. The resulting amide 17 can be deprotected(N-Cbz), and then coupled to 9a to form the same 15. The N-Boc of 15 canbe removed to give the key intermediate amine 19. One target can besynthesized via a reductive amination with 5 to yield 20. The secondtarget can be synthesized by performing another reductive amination togive 21.

[0466] A series of compounds of formulas 23 and 24 can be synthesized asshown in Scheme 4. The key intermediate 19 can be alkyated via reductiveamination to give 22. The first target can be synthesized by coupling 22with 9 to give 23. The second target can be synthesized by directcoupling of 19 with 9 to afford 24.

[0467] A series of compounds of formulas 32 and 34 are prepared via themethods shown in Scheme 5. An amine 25 (for example, the commerciallyavailable 2-benzyloxycyclopentylamine) can be protected as the carbamate26 via Boc₂O. Removal of the benzyl group affords the alcohol 27, whichcan be converted to the mesylate 28. The mesylate can be displaced withNaN₃ to provide the azide 29. This can be reduced to the keyintermediate 30. This amine can be coupled with 9 to afford the amide31. The first target can be synthesized by deprotection with TFAfollowed by coupling with 3 to give 32. Another target can besynthesized from 30 by first performing a reductive amination to give33. The amine 33 can be coupled to 9, deprotected with TFA, and coupledwith 3 to afford the target 34.

[0468] A series of compounds of formulas 39 and 40 are synthesized asshown in Scheme 6. The key intermediate 30 can be protected as the Cbzcarbamate 35 via Cbz₂O.

[0469] The Boc group can be removed, and the acid 3 can be coupled toprovide amide 37. The amide 37 can be deprotected to the amine 38, and areductive amination can be performed to give the first target 39. Thesecond target can be synthesized via another reductive amination on 39to afford 40.

[0470] As shown in Schemes 5 and 6, intermediate 30 can be convertedinto several target molecules. As a key intermediate, 30 can besynthesized several different ways. As shown in Scheme 7, a cyclicolefin 41 [many are available for this:1-carbobenzyloxy-1,2,3,6-tetrahydropyridine (D'Andrea et al., J. Org.Chem. 1991, 56, 3133), 4-aminocyclohexene derivatives (Bisagni et al.,J. Heterocycl. Chem. 1990, 27, 1801 or Pfister et al. Synthesis 1983,38-40), or 3-pyrroline derivatives (Lai et al., J. Med. Chem. 1997, 40,226)] can be oxidized to the epoxide 42 (Jacobsen et al., J. Org. Chem.1997, 62, 4197). This can be opened with NaN₃ to give the azide 43,which can be reduced. The resulting amine 44 can be protected as theN-Boc 45. This can be converted to the mesylate 46 and then the azide47. In the final step, the azide 47 can be reduced to the keyintermediate 30.

[0471] A series of compounds of formula 58 are synthesized as shown inScheme 8. The cyclic, unsaturated acid 48 can be converted into the2-aminocyclocarboxylate 51 via two routes. In the first route,esterification followed by a Michael reaction (Davies et al., J. Chem.Soc. Perkin Trans. 1,1994, 1411) gives 50. Simple hydrogenation givesthe 2-aminocyclocarboxylate 51. In the second route, the Michaelreaction (Schneider et al., Chem Ber. 1959, 92, 1594) can be performedwith ammonia to give 51 after esterification. Going forward, a Cbz group(or another appropriate protecting group) can be installed understandard conditions to afford 52. Enolization of the ester with LDA (oranother appropriate base) followed by alkylation gives the substituted53. The ester is then removed to afford the free acid 54. A Curtius(Yamada et al., Tetrahedron 1974, 30, 2151) or Hofmann reaction (Zhanget al., J. Org. Chem. 1997, 62, 6918) can then be performed to give thediamino derivative 55 (as in 35, Scheme 6). After removal of the Bocgroup, the right-side piece 3 can be coupled on to give the amide 57.This can be elaborated as shown in Scheme 3, 4, 5, and 6 to give thedesired target 58.

[0472] A series of comounds of formula 64 are synthesized as shown inScheme 9. In this case, intermediate 52 (or another appropriateprotecting group for Cbz) from Scheme 8 can be used as a starting point.Enolization of the ester with LDA (or another appropriate base) followedby alkylation gives the substituted 59. The ester is then removed toafford the free acid 60. A Curtius (Yamada et al., Tetrahedron 1974, 30,2151) or Hofmann reaction (Zhang et al., J. Org. Chem. 1997, 62, 6918)can then be performed to give the diamino derivative 61 (as in 35,Scheme 6). The Cbz can be removed via hydrogenation to give the freeamine 62. As before, this material can be coupled to the right-sidepiece 3 to give the amide 63. This can then be elaborated as shown inScheme 3, 4, 5, and 6 to give the desired target 64.

[0473] A series of compounds of formula 74 are synthesized as shown inScheme 10. A cyclic ester acid 65 can be alkylated with LDA (or anotherappropriate base) and the electrophile R¹¹-LG to give 66. This materialcan be esterified via the isourea (Mathias Synthesis 1979, 561) toafford the diester 67. Hydrolysis leads to the acid 68, which canundergo a Curtius or a Hofmann to give 69 (or another appropriateprotecting group for Cbz). Once again, the ester can be alkylated withthe electrophile R¹²-LG to provide 70. The tert-butyl ester can beremoved to the acid 71, and a Curtius or Hofmann reaction provides theamine 72 (much like 35, Scheme 6). As before, 72 can be coupled to theright-side piece 3 to give the amide 73. This can then be elaborated asshown in Scheme 3, 4, 5, and 6 to give the desired target 74.

[0474] When required, separation of the racemic material can be achievedby HPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605.

[0475] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments which aregiven for illustration of the invention and are not intended to belimiting thereof.

EXAMPLES

[0476] Abbreviations used in the Examples are defined as follows: “1×”for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius,“g” for gram or grams, “mg” for milligram or milligrams, “mL” formilliliter or milliliters, “¹H” for proton, “h” for hour or hours, “M”for molar, “min” for minute or minutes, “MHz” for megahertz, “MS” formass spectroscopy, “NMR” for nuclear magnetic resonance spectroscopy,“rt” for room temperature, “tlc” for thin layer chromatography, “v/v”for volume to volume ratio. “R” and “S” are stereochemical designationsfamiliar to those skilled in the art.

Example 1N-[2-[[(1S,2S)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0477] (1a) N-tert-Butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine (C. Wuet al., Bioorg. Med. Chem. 1997, 5, 1925) (3.0 g) was dissolved in DMFprior to the addition of, 4-methylmorpholine (7.7 mL) and[[3-(trifluoromethyl)benzoyl]amino]acetic acid (3.8 g). This solutionwas cooled to 0° C., and BOP (6.8 g) was added in portions. The reactionwas warmed to rt and was stirred overnight. The reaction was quenchedwith water and EtOAc. The EtOAc layer was washed with 1 N HCl solution,NaHCO₃ solution, and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the resulting residue gave theN-Boc derivative[(1S,2S)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid 1,1-dimethylethyl ester (5.0 g). MS found: (M+Na)⁺=466.3.

[0478] (1b) The above derivative (1a) (5.0 g) was dissloved in CH₂Cl₂(10 mL) and cooled to 0° C. Trifluoroacetic acid (10 mL) was added andthe reaction was warmed to rt. After 1 h, the solvent was removed togive an oily residue. This was re-dissolved in CH₂C¹ ₂ and thenre-concentrated to the amineN-[2-[[(1S,2S)-2-aminocyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(5.0 g). MS found: (M+H)⁺=344.3.

[0479] (1c) The above amine (1b) (110 mg) was dissolved in THF prior tothe addition of Hunigs's base (0.2 mL). Next, 4-chlorobenzaldehyde (30mg) was added along with 4A molecular sieves. After 3 h, NaHB(OAc)₃ (76mg) was added. This mixture was stirred an additional 2 h before thereaction was quenched with NaHCO₃ solution. This was extracted withEtOAc. The EtOAc was dried and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title benzamideN-[2-[[(1S,2S)-2-[[(4-chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(30 mg). MS found: (M+H)⁺=468.2.

Example 2N-[2-[[(1S,2S)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0480] (2a) 2,4-Dimethylbenzaldehyde (0.04 mL) was incorporated into theabove procedure, (1c), to give the title benzamide (35 mg). MS found:(M+H)⁺=462.3.

Example 3N-[2-[[(1S,2S)-2-[[(2,4,6-Trimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0481] (3a) 2,4,6-trimethylbenzaldehyde (0.07 mL) was incorporated intothe above procedure, (1c), to give the title benzamide (30 mg). MSfound: (M+H)⁺=476.4.

Example 4N-[2-[[(1S,2S)-2-[[(4-Benzyloxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0482] (4a) 4-Benzyloxybenzaldehyde (108 mg) was incorporated into theabove procedure, (1c), to give the title benzamide (40 mg). MS found:(M+H)⁺=540.4.

Example 5N-[2-[[(1S,2S)-2-[[(2,4-Difluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0483] (5a) 2,4-Difluorobenzaldehyde (0.06 mL) was incorporated into theabove procedure, (1c), to give the title benzamide (25 mg). MS found:(M+H)⁺=470.3.

Example 6N-[2-[[(1S,2S)-2-[[(2-Chloro-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0484] (6a) 2-Chloro-4-fluorobenzaldehyde (75 mg) was incorporated intothe above procedure, (1c), to give the title benzamide (15 mg). MSfound: (M+H)⁺=486.2.

Example 7N-[2-[[(1S,2S)-2-[[(2-Trifluoromethyl-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0485] (7a) 2-Trifluoromethyl-4-fluorobenzaldehyde (0.06 mL) wasincorporated into the above procedure, (1c), to give the title benzamide(20 mg). MS found: (M+H)⁺=520.2.

Example 8

[0486]N-[2-[[(1S,2S)-2-[[(2,4-Dichlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0487] (8a) 2,4-Dichlorobenzaldehyde (91 mg) was incorporated into theabove procedure, (1c), to give the title benzamide (10 mg). MS found:(M+H)⁺=502.1.

Example 9N-[2-[[(1S,2S)-2-[[(2-Fluoro-6-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0488] (9a) 2-Fluoro-6-trifluoromethylbenzaldehyde (0.06 mL) wasincorporated into the above procedure, (1c), to give the title benzamide(30 mg). MS found: (M+H)⁺=520.2.

Example 10N-[2-[[(1S,2S)-2-[[(2-Chloro-5-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0489] (10a) 2-Chloro-5-trifluoromethylbenzaldehyde (0.083 mL) wasincorporated into the above procedure, (1c), to give the title benzamide(20 mg). MS found: (M+H)⁺=536.2.

Example 11N-[2-[[(1S,2S)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0490] (11a) 1-Naphthaldehyde (0.05 mL) was incorporated into the aboveprocedure, (1c), to give the title benzamide (6 mg). MS found:(M+H)⁺=484.3.

Example 12N-[2-[[(1S,2S)-2-[bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0491] (12a) 3-Furaldehyde (0.03 mL) was incorporated into the aboveprocedure, (1c), to give the title benzamide (30 mg). MS found:(M+H)⁺=504.3.

Example 13N-[2-[[(1S,2S)-2-[(2,4-Dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0492] (13a) The title benzamide from Example (2a) (25 mg) was dissolvedin THF prior to the addition of Hunigs's base (0.01 mL). Next, 37%formaldehyde (0.02 mL) was added along with 4A molecular sieves. After 3h, NaHB(OAc)₃ (46 mg) was added. This mixture was stirred an additional2 h before the reaction was quenched with NaHCO₃ solution. This wasextracted with EtOAc. The EtOAc was dried and concentrated. Reversephase HPLC purification (gradient elution, water/acetonitrile/TFA) ofthe resulting residue provided the title benzamideN-[2-[[(1S,2S)-2-[(2,4-dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(10 mg). MS found: (M+H)⁺=476.3.

Example 14N-[2-[[(1S,2S)-2-[(4-Chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0493] (14a) The title benzamide from Example 1 (21 mg) was dissolved inTHF prior to the addition of Hunigs's base (0.01 mL). Next, 37%formaldehyde (0.017 mL) was added along with 4A molecular sieves. After3 h, NaHB(OAc)₃ (38 mg) was added. This mixture was stirred anadditional 2 h before the reaction was quenched with NaHCO₃ solution.This was extracted with EtOAc. The EtOAc was dried and concentrated.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamideN-[2-[[(1S,2S)-2-[(4-chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(10 mg). MS found: (M+H)⁺=482.3.

Example 15N-[2-[[(cis)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0494] (15a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine(prepared in an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine see: C. Wu et al.,Bioorg. Med. Chem. 1997, 5, 1925) was substituted into Example 1, step(1a), and 2,4-dimethylbenzaldehyde (0.1 mL) was substituted into step(1c) to give the title benzamideN-[2-[[(cis)-2-[[(2,4-dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(40 mg). MS found: (M+H)⁺=462.4.

Example 16N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0495] (16a) 4-Chlorobenzaldehyde (167 mg) was incorporated into Example15 to give the title benzamide (30 mg). MS found: (M+H)⁺=468.3.

Example 17N-[2-[[(cis)-2-[[(4-Nitrophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0496] (17a) 4-Nitrobenzaldehyde (67 mg) was incorporated into Example15 to give the title benzamide (45 mg). MS found: (M+H)⁺=479.3.

Example 18N-[2-[[(cis)-2-[[(4-Isopropylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0497] (18a) 4-Isopropylbenzaldehyde (0.07 mL) was incorporated intoExample 15 to give the title benzamide (20 mg). MS found: (M+H)⁺=476.3.

Example 19N-[2-[[(cis)-2-[[(4-Trifluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0498] (19a) 4-Trifluorobenzaldehyde (0.05 mL) was incorporated intoExample 15 to give the title benzamide (40 mg). MS found: (M+H)⁺=502.3.

Example 20N-[2-[[(cis)-2-[[(4-Trifluoromethoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0499] (20a) 4-Trifluoromethoxybenzaldehyde (0.09 mL) was incorporatedinto Example 15 to give the title benzamide (50 mg). MS found:(M+H)⁺=518.2.

Example 21N-[2-[[(cis)-2-[[(4-Phenoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0500] (21a) 4-Phenoxybenzaldehyde (0.1 mL) was incorporated intoExample 15 to give the title benzamide (40 mg). MS found: (M+H)⁺=526.2.

Example 22N-[2-[[(cis)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0501] (22a) 1-Naphthaldehyde (0.05 mL) was incorporated into Example 15to give the title benzamide (30 mg). MS found: (M+H)⁺=484.3.

Example 23N-[2-[[(cis)-2-[[(2-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0502] (23a) 2-Naphthaldehyde (53 mg) was incorporated into Example 15to give the title benzamide (20 mg). MS found: (M+H)⁺=484.3.

Example 24N-[2-[[(cis)-2-[[(3-Indolyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0503] (24a) Indole-3-carboxaldehyde (65 mg) was incorporated intoExample 15 to give the title benzamide (10 mg). MS found: (M+H)⁺=473.3.

Example 25N-[2-[[(cis)-2-[[1-(4-Chlorophenyl)ethyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0504] (25a) 2′-Chloroacetophenone (0.2 mL) was incorporated intoExample 15 to give the title benzamide (20 mg). MS found: (M+H)⁺=482.2.

Example 26N-[2-[[(cis)-2-[Bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0505] (26a) 3-Furaldehyde (0.04 mL) was incorporated into Example 15 togive the title benzamide (30 mg). MS found: (M+H)⁺=504.3.

Example 27N-[2-[[(1S,2R)-2-[(4-Chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0506] (27-a) (1S, 2S)-1-Amino-2-benzyloxycyclopentane (12.1g)(Lancaster Synthesis Inc.) was dissolved in THF prior to the addition ofwater (58 mL) and Et₃N (35.4 mL). After cooling to 0° C., Boc₂O (15.23g) in THF (58 mL) was added dropwise. The reaction was warmed to rt andwas stirred overnight. The THF was removed and EtOAc was added. Thissolution was washed with 1M HCl and brine. The EtOAc was dried (MgSO₄),filtered, and concentrated to give (1S,2S)-N-(t-butoxycarbonyl)-2-benzyloxycyclopentane (18.4 g). MS found:(M+Na)⁺=314.2.

[0507] (27b) The above material (27a) (18.4 g) was dissolved in MeOH (90mL) prior to the addition of 20% Pd(OH)₂/C. This reaction was placed onthe Parr apparatus at 60 psi hydrogen pressure. After shaking 4.25 h,the Pd/C was filtered and the solution was concentrated (13.4 g). Aportion of this material (12.7 g) was dissolved in CH₂Cl₂ prior to theaddition of Et₃N (26.5 mL). After cooling to 0° C., MsCl (7.4 mL) wasadded dropwise. This continued stirring for 2.5 h, before water wasadded. The CH₂Cl₂ layer was also washed with NaHCO₃ solution and brine.The CH₂Cl₂ was dried (MgSO₄), filtered, and concentrated. This materialwas dissolved in DMF (180 mL) prior to the addition of NaN₃. Theresulting solution was heated at 85° C. for 2 h. After cooling, EtOAcwas added along with brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated to a solid. This solid was dissolved in MeOH (100 mL) priorto the addition of 10% Pd/C. A hydrogen ballooon was attached, and themixture stirred overnight. The Pd/C was filtered off, and the MeOH wasremoved to give (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine (6 g). MS found:(M+H)⁺=201.4.

[0508] (27c) 4-Chlorobenzoic acid (258 mg) was dissolved in DMF (8 mL)prior to the addition of Hunig's base (1.0 mL). After cooling to 0° C.,BOP Reagent (729 mg) was added. This was stirred for 15 min before (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine, (27b), (300 mg)was added as a DMF solution (2 mL). The resulting mixture warmed to rtand was stirred overnight. EtOAc was added along with 1 N HCl solution.The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. The resultingmaterial was dissolved in CH₂Cl₂ (10 mL) and cooled to 0° C. TFA (1.2mL) was added and the reaction was stirred for 2 h. This solution wasconcentrated prior to the addition of DMF (8 mL). After cooling to 0°C., Hunig's base (1 mL) and [[3-(trifluoromethyl)benzoyl]amino]aceticacid (386 mg) were added. BOP Reagent (655 mg) was added next, and themixture was stirred overnight. EtOAc was added along with 1 N HClsolution. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution, andbrine. The EtOAc was dried (MgSO4), filtered, and concentrated. This wasstirred in 1:1 EtOAc/hexane and then filtered to give the titlebenzamideN-[2-[[(1S,2R)-2-[(4-chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(310 mg) as a solid. MS found: (M+H)⁺=468.2.

Example 28N-[2-[[(1S,2R)-2-[(4-(Methylthio)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0509] (28a) 4-(Methylthio)benzoic acid (277 mg) was incorporated intoExample 27, step (27c), to give the title benzamide (320 mg). MS found:(M+H)⁺=480.2.

Example 29N-[2-[[(1S,2R)-2-[(4-(Methylsulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0510] (29a) 4-(Methylsulfonyl)benzoic acid (330 mg) was incorporatedinto Example 27, step (27c), to give the title benzamide (209 mg). MSfound: (M+H)⁺=512.1.

Example 30N-[2-[[(1S,2R)-2-[(4-Iodobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0511] (30a) 4-Iodobenzoic acid (409 mg) was incorporated into Example27, step (27c), and HPLC purification (gradient elution,water/acetonitrile/TFA) gave the title benzamide (20 mg). MS found:(M+H)⁺=431.0.

Example 31N-[2-[[(1S,2R)-2-[(4-(Aminosulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0512] (31a) 4-Carboxybenzenesulfonamide (79 mg) was incorporated intoExample 27, step (27c), and the resulting residue was purified byreverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) to provided the title benzamide (140 mg). MSfound: (M+Na)⁺=535.1.

Example 32N-[2-[[(1S,2R)-2-[[(4-Chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0513] (32a) (1S, 2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine,(27b), (1.0 g) was dissolved in THF (5 mL) and water (5 mL) prior to theaddition of Et₃N (2.8 mL). After cooling to 0° C., Cbz₂O (1.6 g) in THFwas added. This mixture was warmed to rt and was stirred overnight. TheTHF was removed and EtOAc was added. The EtOAc layer was washed with 1 NHCl and brine. The EtOAc was dried (MgSO₄), filtered, and concentratedto a white solid (1.7 g). This white solid was dissolved in CH₂Cl₂ (20mL) and cooled to 0° C. TFA (4 mL) was added and the reaction wasstirred for 2 h. This solution was concentrated prior to the addition ofDMF (10 mL). After cooling to 0° C., 4-methylmorpholine (2.2 mL) and[[3-(trifluoromethyl)benzoyl]amino]acetic acid (386 mg) were added. BOPReagent (2.5 g) was added, and the mixture was stirred overnight. EtOAcwas added along with 1 N HCl solution. The EtOAc layer was washed with 1N HCl, NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄),filtered, and concentrated. The resulting residue was purified by flashchromatography to afford the N-Cbz derivative[(1R,2S)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclopentyl]carbamic acid phenylmethyl ester (1.3 g).

[0514] (32b) The above derivative (32a) (1.2 g) was dissolved in MeOH(100 mL) prior to the addition of 20% Pd(OH)₂ (240 mg). The solution wasplaced on a Parr shaker at 55 psi hydrogen pressure overnight. ThePd(OH)₂ was filtered off and the solution was concentrated. A portion ofthe resulting residue (132 mg) was dissolved in THF prior to theaddition of acetic acid (0.23 mL) and 4-chlorobenzaldehyde (85 mg).After 45 min, NaHB(OAc)₃ was added. This mixture was stirred overnightbefore the solution was concentrated. EtOAc was added. The EtOAc layerwas washed with NaHCO₃ solution. The EtOAc was dried (MgSO₄), filtered,and concentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamideN-[2-[[(1S,2R)-2-[[(4-chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(63 mg). MS found: (M+H)⁺=454.1.

Example 33

[0515]N-[2-[[(1S,2R)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0516] (33a) 2,4-Dimethylbenzaldehyde (0.1 mL) was incorporated intoExample 32, step (32b), to give the title benzamide (47 mg). MS found:(M+H)⁺=448.2.

Example 34 N-[2-[(1S,2R)-2-[[(4-Methylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0517] (34a) 4-Methylbenzaldehyde (0.08 mL) was incorporated intoExample 32, step (32b), to give the title benzamide (43 mg). MS found:(M+H)⁺=434.1.

Example 35N-[2-[[(cis)-2-[(4-Chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0518] (35a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine(prepared in an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (5.0 g) was dissolved in DMF (70mL). After cooling to 0° C., 4-methylmorpholine (7.7 mL) and[[3-(trifluoromethyl)benzoyl]amino]acetic acid (5.8 g) were added. BOPReagent (11.3 g) was added, and the mixture was stirred overnight. EtOAcwas added along with 1 N HCl solution. The EtOAc layer was washed with 1N HCl, NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄),filtered, and concentrated. The resulting residue was purified by flashchromatography to afford the N-Boc derivative[(cis)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamic acid 1,1-dimethylethyl ester (8.5 g). MS found: (M+H)⁺=444.1.

[0519] (35b) A portion of the above derivative (35a) (5 g) was dissolvedin CH₂Cl₂ (10 mL) and cooled to 0° C. TFA (10 mL) was added and thereaction was stirred for 2 h. This solution was concentrated and aportion (128 mg) was dissolved in DMF (5 mL). After cooling to 0° C.,4-methylmorpholine (0.15 mL) and 4-chlorobenzoic acid (53 mg) wereadded. BOP Reagent (136 mg) was added next, and the mixture was stirredovernight. EtOAc was added along with 1 N HCl solution. The EtOAc layerwas washed with 1 N HCl, NaHCO₃ solution, and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) of the resulting residueprovided the title benzamideN-[2-[[(cis)-2-[(4-chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(30 mg). MS found: (M+H)⁺=482.2.

Example 36N-[2-[[(cis)-2-[(4-Methylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0520] (36a) 4-Methylbenzoic acid (41 mg) was incorporated into Example35, step (35b), to give the title benzamide (40 mg). MS found:(M+Na)⁺=484.2.

Example 37N-[2-[[(cis)-2-[(4-Fluorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0521] (37a) 4-Fluorobenzoic acid (45 mg) was incorporated into Example35, step (35b), to give the title benzamide (10 mg). MS found:(M+H)⁺=466.2.

Example 38N-[2-[[(cis)-2-[Benzoylamino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0522] (38a) Benzoic acid (45 mg) was incorporated into Example 35, step(35b), to give the title benzamide (15 mg). MS found: (M+H)⁺=448.2.

Example 39N-[2-[[(cis)-2-[(4-Bromobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0523] (39a) 4-Bromobenzoic acid (58 mg) was incorporated into Example35, step (35b), to give the title benzamide (18 mg). MS found:(M+H)⁺=528.1.

Example 40N-[2-[[(cis)-2-[(4-Phenoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0524] (40a) 4-Phenoxybenzoic acid (67 mg) was incorporated into Example35, step (35b), to give the title benzamide (10 mg). MS found:(M+H)⁺=540.2.

Example 41N-[2-[[(cis)-2-[(4-Trifluoromethylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0525] (41a) 4-Trifluorobenzoic acid (67 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (38 mg). MS found:(M+H)⁺=516.2.

Example 42N-[2-[[(cis)-2-[(5-Benzotriazolecarbonyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0526] (42a) Benzotriazole-5-carboxylic (45 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (8 mg). MS found:(M+H)⁺=489.2.

Example 43N-[2-[[(cis)-2-[(4-Iodobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0527] (43a) 4-Iodobenzoic acid (74 mg) was incorporated into Example35, step (35b), to give the title benzamide (25 mg). MS found:(M+H)⁺=574.2.

Example 44

[0528]N-[2-[[(cis)-2-[(4-Cyanobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0529] (44a) 4-Cyanobenzoic acid (49 mg) was incorporated into Example35, step (35b), to give the title benzamide (40 mg). MS found:(M+H)⁺=473.3.

Example 45N-[2-[[(cis)-2-[(4-Trifluoromethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0530] (45a) 4-Trifluoromethoxybenzoic acid (55 mg) was incorporatedinto Example 35, step (35b), to give the title benzamide (15 mg). MSfound: (M+H)⁺=532.2.

Example 46N-[2-[[(cis)-2-[(4-Formylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0531] (46a) 4-Formylbenzoic acid (36 mg) was incorporated into Example35, step (35b), to give the title benzamide (10 mg). MS found:(M+H)⁺=476.3.

Example 47N-[2-[[(cis)-2-[(4-Carbomethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0532] (47a) 4-Carbomethoxybenzoic acid (38 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (55 mg). MS found:(M+H)⁺=506.2.

Example 48N-[2-[[(cis)-2-[(4-Nitrobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0533] (48a) 4-Nitrobenzoic acid (140 mg) was incorporated into Example35, step (35b), to give the title benzamide (200 mg). MS found:(M+H)⁺=493.2.

Example 49N-[2-[[(cis)-2-[(4-Aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0534] (49a) The above material, Example 48, (10 mg) was dissolved inMeOH prior to the addition of 10% Pd/C. A hydrogen balloon was attachedand the mixture was stirred overnight. The Pd/C was filtered off and theMeOH removed to give the title benzamideN-[2-[[(cis)-2-[(4-aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(5 mg). MS found: (M+H)⁺=463.2.

Example 50N-[2-[[(cis)-2-[(4-Methoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0535] (50a) 4-Methoxybenzoic acid (31 mg) was incorporated into Example35, step (35b), to give the title benzamide (47 mg). MS found:(M+H)⁺=478.3.

Example 51N-[2-[[(cis)-2-[(4-Methylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0536] (51a) 4-Methylthiobenzoic acid (38 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (10 mg). MS found:(M+H)⁺=494.2.

Example 52N-[2-[[(cis)-2-[(4-Methylsulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0537] (52a) 4-Methylsulfonylbenzoic acid (45 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (40 mg). MS found:(M+H)⁺=526.2.

Example 53N-[2-[[(cis)-2-[(4-Aminosulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0538] (53a) 4-Aminosulfonylbenzoic acid (50 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (40 mg). MS found:(M+H)⁺=527.2.

Example 54N-[2-[[(cis)-2-[(4-Isopropylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0539] (54a) 4-Isopropylbenzoic acid (45 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (30 mg). MS found:(M+H)⁺=490.3.

Example 55N-[2-[[(cis)-2-[(4-Phenylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0540] (55a) 4-Phenylthiobenzoic acid (63 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (27 mg). MS found:(M+H)⁺=556.2.

Example 56N-[2-[[(cis)-2-[(4-(N,N-diethylsulfamoyl)benzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0541] (56a) N,N-Diethyl-4-sulfamoylbenzoic acid (63 mg) wasincorporated into Example 35, step (35b), to give the title benzamide(30 mg). MS found: (M+H)⁺=583.3.

Example 57N-[2-[[(cis)-2-[(4-Trifluoromethylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0542] (57a) 4-Trifluoromethylthiobenzoic acid (117 mg) was incorporatedinto Example 35, step (35b), to give the title benzamide (20 mg). MSfound: (M+H)⁺=548.2.

Example 58N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0543] (58a) 1-(N-(t-butoxycarbonyl))-1,2-(cis)-cyclopropanediaminehydrogen chloride (Langlois et al, Bioorg. Med. Chem. 2000, 8, 321) (850mg) was dissolved in DMF (10 mL). After cooling to 0° C.,4-methylmorpholine (2.7 mL) and[[3-(trifluoromethyl)benzoyl]amino]acetic acid (1.4 g) were added. BOPReagent (2.4 g) was added, and the mixture was stirred overnight. EtOAcwas added along with 1 N HCl solution. The EtOAc layer was washed with 1N HCl, NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄),filtered, and concentrated. The resulting residue was purified by flashchromatography to afford the N-Boc derivative[(cis)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclopropyl]carbamicacid 1,1-dimethylethyl ester (1.5 g). MS found: (M+Na)⁺=424.1.

[0544] (58b) The above derivative (58a) (1.2 g) was dissloved in CH₂C₂and cooled to 0° C. Trifluoroacetic acid was added and the reaction waswarmed to rt. After 2 h, the solvent was removed. A portion of theresulting residue (100 mg) was dissolved in THF prior to the addition ofacetic acid (0.014 mL), 4-chlorobenzaldehyde (34 mg), and 4A molecularsieves (100 mg). After 30 min, NaHB(OAc)₃ (76 mg) was added, and themixture was stirred overnight at rt. EtOAc and NaHCO₃ solution wereadded. This was extracted with EtOAc. The EtOAc was dried andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamide,N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(10 mg). MS found: (M+H)⁺=550.1.

Example 59N-[2-[[(cis)-2-[[(3,4-Dimethylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0545] (59a) 3,4-Dimethylbenzaldehyde (0.03 mL) was incorporated intoExample 58, step (58b), to give the title benzamide (20 mg). MS found:(M+H)⁺=420.1.

Example 60N-[2-[[(cis)-2-[[(4-Methylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

[0546] (60a) 4-Methylbenzaldehyde (28 mg) was incorporated into Example58, step (58b), to give the title benzamide (10 mg). MS found:(M+H)⁺=406.1.

Example 612-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodobenzamide

[0547] (61a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine(prepared in an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (10.7 g) was dissolved in DMF(167 mL). After cooling to 0° C., diisopropylethylamine (35 mL) andN-Cbz-Gly-OH (12.1 g) were added. HATU Reagent (21.9 g) was added, andthe mixture was stirred for 4 days (out of convenience). EtOAc was addedalong with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl,NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated (14.6 g). The resulting residue was dissloved in CH₂Cl₂ (20mL) prior to the addition of TFA (20 mL). After 15 min, the solution wasconcentrated to a foam. This material was dissolved in DMF (70 mL).After cooling to 0° C., diisopropylethylamine (25 mL) and4-aminosulfonylbenzoic acid (8.7 g) were added. BOP Reagent (19.2 g) wasadded, and the mixture was stirred overnight. EtOAc was added along with1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. CH₂Cl₂ was added and the off-white solid was collected togive benzyl(cis)-2-[(2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethylcarbamate(8.1 g). MS found: (M+H)⁺=511.1.

[0548] (61b) The material from above benzyl(cis)-2-[(2-{[4-(aminosulfonyl)benzoyl]amino]cyclohexyl)amino]-2-oxoethylcarbamate(217 mg) was dissolved in 30% HBr/AcOH (5 mL) at rt. After 1 h, Et₂O wasadded and the solid was collected to giveN-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide. MS found: (M+H)⁺=355.2.

[0549] (61c) The above material, (61b),N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide (59 mg) was dissolved in DMF (1 mL). After cooling to0° C., diisopropylethylamine (0.1 mL) and 2-amino-5-iodobenzoic acid (43mg) were added. BOP Reagent (72 mg) was added, and the mixture wasstirred overnight. EtOAc was added along with NaHCO₃ solution. The EtOAcwas dried (MgSO₄), filtered, and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title benzamide2-amino-N-{2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}-5-iodobenzamide(6 mg). MS found: (M+Na)⁺=622.2.

Example 622-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-chlorobenzamide

[0550] (62a) 2-Amino-5-chlorobenzoic acid (65 mg) was incorporated intoExample 61, step (61c), to give the title benzamide (8 mg). MS found:(M+Na)⁺=530.3.

Example 63N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-chlorobenzamide

[0551] (63a) 3-Chlorobenzoic acid (43 mg) was incorporated into Example61, step (61c), to give the title benzamide (50 mg). MS found:(M+H)⁺=515.2.

Example 64N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-trifluoromethoxybenzamide

[0552] (64a) 3-Trifluoromethoxybenzoic acid (57 mg) was incorporatedinto Example 61, step (61c), to give the title benzamide (47 mg). MSfound: (M+H)⁺=543.1.

Example 65 Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate

[0553] (65a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid(87 mg) (Takagishi et al., Synlett 1992, 360) was incorporated intoExample 61, step (61c), to give the title benzamide (150 mg). MS found:(M+Na)⁺=664.3.

Example 662-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamidetrifluoroacetate

[0554] (66a) The material from above, (65a), (125 mg) was dissolved inCH₂Cl₂ (5 mL) prior to the addition of TFA (5 mL). After 1 h, thesolution was concentrated. Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of a portion (25 mg) of the resultingresidue provided the title benzamide (10 mg). MS found: (M+Na)⁺=564.2.

Example 674-(Aminosulfonyl)-N-((cis)-2-{[({[2-(trifluoromethyl)anilino]carbonyl}amino)acetyl]amino}cyclohexyl)benzamide

[0555] (67a)N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide, (61b), (100 mg) was dissolved in DMF (3 mL) prior tothe addition of 4-methylmorpholine (0.13 mL) and 2-trifluoromethylphenylisocyanate (0.05 mL). After stirring overnight, EtOAc was added and thesolution was washed with 1N HCl. The EtOAc was dried, filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamide (50 mg). MS found: (M+Na)⁺=564.3.

Example 684-(Aminosulfonyl)-N-{(cis)-2-[({[(3-chlorophenyl)sulfonyl]amino}acetyl)amino]cyclohexyl}benzamide

[0556] (68a)N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide, (61b), (70 mg) was dissolved in DMF (2.5 mL) prior tothe addition of 3-chlorobenzenesulfonyl chloride (51 mg). After stirringovernight, EtOAc was added and the solution was washed with 1N HCl. TheEtOAc was dried, filtered, and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title benzamide (25 mg). MS found: (M+H)⁺=530.1.

Example 69 Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate

[0557] (69a) 2-(Ethyloxycarbonyl)amino-5-iodobenzoic acid (185 mg) wasincorporated into Example 61, step (61c), to give the titlephenylcarbamate (87 mg). MS found: (M−H)⁻=670.9.

Example 70 Methyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate

[0558] (70a) 2-(Methyloxycarbonyl)amino-5-iodobenzoic acid (177 mg) wasincorporated into Example 61, step (61c), to give the titlephenylcarbamate (67 mg). MS found: (M−H)⁻=656.9.

Example 71 Tert-butylN-Methyl-2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate

[0559] (71a)N-Methyl-2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (106mg) was incorporated into Example 61, step (61c), to give the titlephenylcarbamate (50 mg). MS found: (M+Na)⁺=678.2.

Example 72 Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate

[0560] (72a) 2-(Ethyloxycarbonyl)amino-5-trifluoromethyl benzoic acid(61 mg) was incorporated into Example 61, step (61c), to give the titlephenylcarbamate (12 mg). MS found: (M+Na)⁺=636.1.

Example 732-(Benzylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0561] (73a) 2-(Benzylamino)-5-trifluoromethyl benzoic acid (65 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(45 mg). MS found: (M+Na)⁺=654.2.

Example 742-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0562] (74a) 2-(Ethylamino)-5-trifluoromethyl benzoic acid (51 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(45 mg). MS found: (M+Na)⁺=592.1.

Example 752-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0563] (75a) 2-(Methylamino)-5-trifluoromethyl benzoic acid (25 mg) wasincorporated into Example 61, step (61c), to give the title benzamide (8mg). MS found: (M+Na)⁺=578.2.

Example 762-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-bromoBenzamide

[0564] (76a) 2-Amino-5-bromo benzoic acid (79 mg) was incorporated intoExample 61, step (61c), to give the title benzamide (69 mg). MS found:(M+H)⁺=554.1.

Example 77 Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethoxy)phenylcarbamate

[0565] (77a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethoxybenzoic acid(42 mg) was incorporated into Example 61, step (61c), to give the titlephenylcarbamate (45 mg). MS found: (M+Na)⁺=680.2.

Example 782-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethoxyBenzamide

[0566] (78a) The material from above, (77a), (25 mg) was dissolved inCH₂Cl₂ (3 mL) prior to the addition of TFA (1.5 mL). After 1 h, thesolution was concentrated. Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the resulting residue provided thetitle benzamide (20 mg). MS found: (M+Na)⁺=580.1.

Example 792-(Allylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0567] (79a) 2-(allylamino)-5-trifluoromethyl benzoic acid (50 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(62 mg). MS found: (M+Na)⁺=604.1.

Example 802-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0568] (80a) 2-((2-methyl-2-propenyl)amino)-5-trifluoromethyl benzoicacid (52 mg) was incorporated into Example 61, step (61c), to give thetitle benzamide (40 mg). MS found: (M+Na)⁺=618.1.

Example 812-(cyclopropylmethylene)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0569] (81a) 2-(cyclopropylmethylene)amino-5-trifluoromethyl benzoicacid (52 mg) was incorporated into Example 61, step (61c), to give thetitle benzamide (20 mg). MS found: (M+Na)⁺=618.2.

Example 822-(butyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0570] (82a) 2-(butyl)amino-5-trifluoromethyl benzoic acid (53 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(20 mg). MS found: (M+Na)⁺=620.1.

Example 832-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0571] (83a) 2-(propyl)amino-5-trifluoromethyl benzoic acid (50 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(59 mg). MS found: (M+Na)⁺=606.2.

Example 842-((2-methyl-2-propyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0572] (84a) 2-((2-methyl-2-propyl)amino)-5-trifluoromethyl benzoic acid(50 mg) was incorporated into Example 61, step (61c), to give the titlebenzamide (50 mg). MS found: (M+Na)⁺=620.2.

Example 852-((aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0573] (85a) 2-(aminocarbonyl)amino-5-trifluoromethyl benzoic acid (60mg) was incorporated into Example 61, step (61c), to give the titlebenzamide (7 mg). MS found: (M+Na)⁺=665.1.

Example 862-(acetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0574] (86a) 2-acetylamino-5-trifluoromethyl benzoic acid (77 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(35 mg). MS found: (M+H)⁺=642.1.

Example 872-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]-amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylBenzamide

[0575] (87a) 2-Methylamino-5-iodo benzoic acid (127 mg) was incorporatedinto Example 61, step (61c), to give the title benzamide (20 mg). MSfound: (M+H)⁺=614.1.

Example 882-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylBenzamide

[0576] (88a) 2-Ethylamino-5-iodo benzoic acid (100 mg) was incorporatedinto Example 61, step (61c), to give the title benzamide (25 mg). MSfound: (M+H)⁺=628.1.

Example 892-(Trifluoroacetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylBenzamide

[0577] (89a) 2-Trifluoroacetylamino-5-iodo benzoic acid (77 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(44 mg). MS found: (M+H)⁺=696.1.

Example 902-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-nitroBenzamide

[0578] (90a) 2-amino-5-nitro benzoic acid (28 mg) was incorporated intoExample 61, step (61c), to give the title benzamide (15 mg). MS found:(M+H)⁺=519.1.

Example 91 Iso-propyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate

[0579] (91a) 2-(Iso-propoxycarbonyl)amino-5-iodobenzoic acid (73 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(10 mg). MS found: (M+Na)⁺=686.2.

Example 92 Tert butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino)cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate

[0580] (92a) 2-(Tert-butoxycarbonyl)amino-5-iodobenzoic acid (76 mg) wasincorporated into Example 61, step (61c), to give the title benzamide (9mg). MS found: (M+Na)⁺=722.1.

Example 932-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3,5-dinitroBenzamide

[0581] (93a) 2-amino-3,5-dinitro benzoic acid (45.4 mg) was incorporatedinto Example 61, step (61c), to give the title benzamide (20 mg). MSfound: (M+H)⁺=632.0.

Example 942-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0582] (94a) The material from above, (66a), (20 mg) was dissolved inDMF (5 mL) prior to the addition of N-methylmorpholine (6 mg) andisopropyl isocyanate (4 mg). After 5 h, the solution was loaded onto anHPLC. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (5 mg). MS found:(M+Na)⁺=649.2.

Example 952-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0583] (95a) The material from above, (66a), (20 mg) was dissolved inTHF (2 mL) prior to the addition of 2M K₂CO₃ (0.1 mL) and cyclohexanecarbonyl chloride (0.1 mL). After 15 h, 1 N HCl was added and this wasextracted with ethyl acetate. The ethyl acetate was dried andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (15 mg). MS found:(M+H)⁺=652.2.

Example 962-((Cyclopentylmethylenecarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0584] (96a) Cyclopentylacetyl chloride (0.1 mL) was incorporated intoExample 95, step (95a), to give the title benzamide (10 mg). MS found:(M+H)⁺=652.2.

Example 972-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0585] (97a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine(prepared in an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (8 g) was dissolved in THF (125mL) and water (18 mL). After cooling to 0° C., triethyl amine (6.2 mL)was added followed by Cbz₂O (12.8 g). This was warmed to rt and wasstirred for 18 h. Some of the THF was removed before ethyl acetate wasadded. This solution was washed with brine and then 1 N HCl solution(aq). The EtOAc was dried (MgSO₄), filtered, and concentrated. Theresulting residue was dissloved in CH₂Cl₂ (15 mL). After cooling to 0°C., TFA (15 mL) was added dropwise. After 1 h, the reaction wasconcentrated and 1 N HCl was added. This acidic solution was extractedwith Et₂O. The aqueous solution was taken to pH=13 via addition of solidNa₂CO₃. This solution was extracted with EtOAc. The EtOAc was dried(MgSO₄), filtered, and concentrated to give1-(N-benzyloxycarbonyl)-cis-cyclohexane-1,2-diamine (7.9 g). MS found:(M+H)⁺=249.1.

[0586] (97b) The material from above1-(N-benzyloxycarbonyl)-cis-cyclohexane-1,2-diamine (5 g) was dissolvedin DMF (100 mL). After cooling to 0° C., 4-methylmorpholine (11 mL) andN-Boc-Gly-OH (4.2 g) were added. BOP Reagent (11.6 g) was added, and themixture was stirred at rt for 18 h. The DMF was removed. EtOAc was addedalong with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl,NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated to givecis-[2[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]amino]cyclohexyl]-carbamicacid benzyl ester (9.6 g). MS found: (M+H)⁺=406.3.

[0587] (97c) The material from above (9.6 g) was dissloved in CH₂Cl₂ (20mL). After cooling to 0° C., TFA (10 mL) was added dropwise. After 1 h,the reaction was concentrated. A portion of this residue (5.5 g) wasdissolved in DMF (65 mL). After cooling to 0° C., 4-methylmorpholine(7.2 mL) and 2-(tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid(4.0 g) were added. BOP Reagent (8.7 g) was added, and the mixture wasstirred at rt for 18 h. The DMF was removed. EtOAc was added along with1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue gave[(cis)-2-[[[[(2-(tert-butyloxycarbonylamino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamic acid benzyl ester (5.9 g). MS found: (M+H)⁺=593.3.

[0588] (97d) The material (97c) from above (2 g) was dissloved in CH₂Cl₂(5 mL). After cooling to 0° C., TFA (2.5 mL) was added dropwise. After 1h, the reaction was concentrated. A portion of the resulting residue(500 mg) was dissolved in THF (3 mL) prior to the addition of4-methylmorpholine (0.56 mL). After 5 min, cyclohexanecarbonyl chloride(0.4 mL) was added dropwise. After 30 min, EtOAc and 1 N HCl (aq) wereadded. The EtOAc was dried (MgSO₄), filtered, and concentrated. Thismaterial was dissolved in MeOH (5 mL) prior to the addition of 10% Pd/C(200 mg). A hydrogen balloon was added and the reaction continued tostir. After 1.5 h, the solution was filtered and concentrated to giveN-[2-[[(cis)-2-aminocyclohexyl]amino]-2-oxoethyl]-3-(2-cyclohexylcarbonylamino-5-trifluoromethyl)benzamide(202 mg). MS found: (M+H)⁺=469.4.

[0589] (97e) The material (97d) from above (50 mg) was dissolved in DMF(2 mL). After cooling to 0° C., 4-methylmorpholine (55.5 mg) andp-(methylsulfonyl)benzoic acid (26 mg) were added. After 5 min, BOPReagent (73 mg) was added and the mixture was stirred at rt for 18 h.The DMF was removed. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) provided thetitle benzamide (15 mg). MS found: (M+H)⁺=651.2.

Example 982-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0590] (98a) 4-(Methylthio)benzoic (28 mg) was incorporated into Example97, step (97e), to give the title benzamide (20 mg). MS found:(M+H)⁺=619.3.

Example 992-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0591] (99a) Isopropyl isocyanate (0.3 mL) was incorporated into Example97, step (97d), and reacted for 18 h before being taken forward.Subsequently, 4-(methylthio)benzoic (22 mg) was incorporated intoExample 97, step (97e), to give the title benzamide (20 mg). MS found:(M+H)⁺=594.3.

Example 1002-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0592] (100a) Isopropyl isocyanate (0.3 mL) was incorporated intoExample 97, step (97d), and reacted for 18 h before being taken forward.Subsequently, 4-(methylsulfonyl)benzoic (26 mg) was incorporated intoExample 97, step (97e), to give the title benzamide (9 mg). MS found:(M+H)⁺=541.2.

Example 1012-((Methylsulfonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0593] (101a) Methanesulfonyl chloride (0.3 mL) and pyridine (35 mg)were incorporated into Example 97, step (97d), and reacted for 18 hbefore being taken forward. Subsequently, p-sulfamylbenzoic (43 mg) wasincorporated into Example 97, step (97e), to give the title benzamide(30 mg). MS found: (M+H)⁺=620.1.

Example 1022-((Aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0594] (102a) Sodium cyanate (0.3 mL) in acetic acid and water wereincorporated into Example 97, step (97d), and reacted for 1 h before theprecipitated solid was taken forward. Subsequently, p-sulfamylbenzoic(24 mg) was incorporated into Example 97, step (97e), to give the titlebenzamide (20 mg). MS found: (M+H)⁺=585.2.

Example 103 2-Allylamino-5-trifluoromethylbenzoic Acid

[0595] (103a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid(3.0 g) was dissolved in DMF prior to the addition of K₂CO₃ (2.4 g) andiodomethane (0.8 mL). After 1.5 h, the solution was diluted with EtOAcand was washed with brine solution followed by 1N HCl solution. Theorganic layer was then washed with Na₂CO₃ solution, water, and brine.The organic layer was dried (MgSO₄), filtered, and concentrated to givethe ester as a off-white solid (3.03 g). A portion of this solid wasdissolved in TFA (3.3 mL) and cooled to 0° C. prior to the addition ofTFAA (0.97 mL). After 10 min, crushed ice was added. After an additional30 min, the solid was collected and washed with water. The solid wasdried to give the TFA amide (970 mg). A portion of this solid (385 mg)was dissolved in DMF (2 mL) and K₂CO₃ (338 mg) was added followed byallyl bromide (1.21 mL). The reaction was stirred 18 h before it wasdiluted with EtOAc and washed with 1N HCl and brine. The EtOAc wasdried, filtered, and concentrated. The resulting residue was dissolve inTHF (10 mL) prior to addition of 1N LiOH (10 mL) and 20 drops of MeOH.After 18 h, the THF was removed and the solution was made acidic (pH=5)with 1N HCl. This solution was extracted with EtOAc. The organic layerwas washed with brine, dried, filtered, and concentrated to give2-allylamino-5-trifluoromethylbenzoic acid (265 mg). MS found:(M+H)⁺=246.2.

Example 1042-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0596] (104a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine(prepared in an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (6 g) was dissolved in DMF (80mL). After cooling to 0° C., 4-methylmorpholine (15.4 mL) andN-Cbz-Gly-OH (7.03 g) were added. BOP Reagent (18.6 g) was added, andthe mixture was stirred at rt for 18 h. EtOAc was added along with 1 NHCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution,and brine. The EtOAc was dried (MgSO₄), filtered, and concentrated.Flash chromatography of the resulting residue gavecis-[2[[[[(benzyloxy)carbonyl]amino]acetyl]amino]cyclohexyl]-carbamicacid tert-butyl ester (6.2 g). MS found: (M+H)⁺=406.3. (104b) Thematerial from above (9.6 g) was dissloved in MeOH (60 mL) prior to theaddition of 10% Pd/C (1.5 g). A hydrogen balloon was added and thesolution was stirred for 18 h. The palladium was filtered off and thefiltrate was concentrated. A portion (301 mg) of the resulting residuewas dissolved in DMF (5 mL). After cooling to 0° C., 4-methylmorpholine(0.5 mL) and 2-allylamino-5-trifluoromethylbenzoic acid (Example 103)(226 mg) were added. BOP Reagent (613 mg) was added, and the mixture wasstirred at rt for 18 h. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting gave[(cis)-2-[[[[(2-(allylamino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamic acid tert-butyl ester (364 mg). MS found: (M+Na)⁺=521.2.

[0597] (104c) The material (104b) from above (360 mg) was dissloved in4M HCl/dioxane (10 mL). After stirring for 2 h, the solution wasconcentrated. A portion (50 mg) of the resulting residue was dissolvedin DMF (2.5 mL). After cooling to 0° C., 4-methylmorpholine (58 mg) and4-methylsulfonylbenzoic acid (28 mg) was added. BOP Reagent (76 mg) wasadded, and the mixture was stirred at rt for 18 h. EtOAc was added alongwith 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (15 mg). MS found:(M+H)⁺=581.3.

Example 1052-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0598] (105a) 4-(Methylthio)benzoic (168 mg) was incorporated intoExample 104, step (104c), to give the title benzamide (20 mg). MS found:(M+H)⁺=549.3.

Example 1062-((2-Methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0599] (106a) 3-Bromo-2-methylpropene was substituted for allyl bromidein Example 103 to give2-(2-methyl-2-propenyl)amino-5-trifluoromethylbenzoic acid, which wasincorporated into Example 104, step (104b), to give the title benzamide(20 mg). MS found: (M+H)⁺=595.2

Example 1072-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0600] (107a) 3-Bromo-2-methylpropene was substituted for allyl bromidein Example 103 to give2-(2-methyl-2-propenyl)amino-5-trifluoromethylbenzoic acid, which wasincorporated into Example 104, step (104b). Subsequently,4-(methylthio)benzoic (168 mg) was incorporated into Example 104, step(104c), to give the title benzamide (20 mg). MS found: (M+H)⁺=563.3.

Example 1082-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0601] (108a) For this preparation, Example 104, step 104c, was alteredas follows.[(Cis)-2-[[[[(2-(allylamino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamic acid tert-butyl ester from 104(b) (360 mg) was dissloved in 4MHCl/dioxane (10 mL). After stirring for 2 h, the solution wasconcentrated. A portion (300 mg) of the resulting residue was dissolvedin MeOH (5 mL) and 10% Pd/C was added. A hydrogen balloon was added andthe solution was stirred for 2 h. The palladium was filtered and thesolution was concentrated. A portion (50 mg) of the resulting residuewas dissolved in DMF (2.5 mL). After cooling to 0° C.,4-methylmorpholine (63 mg) and 4-methylsulfonylbenzoic acid (30 mg) wereadded. BOP Reagent (83 mg) was added, and the mixture was stirred at rtfor 18 h. EtOAc was added along with 1 N HCl solution. The EtOAc layerwas washed with 1 N HCl, NaHCO₃ solution, and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) provided the title benzamide(15 mg). MS found: (M+H)⁺=583.3.

Example 1092-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0602] (109a) 4-(Methylthio)benzoic (25 mg) was incorporated intoExample 108 to give the title benzamide (10 mg). MS found: (M+H)⁺=551.3.

Example 1102-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0603] (110a)[(Cis)-2-[[[[(2-((2-methyl-2-propenyl)amino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamic acid tert-butyl ester was incorporated into Example 108 to givethe title benzamide (15 mg). MS found: (M+H)⁺=597.3.

Example 1112-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0604] (11la) 4-(Methylthio)benzoic (25 mg) was incorporated intoExample 110 to give the title benzamide (10 mg). MS found: (M+H)⁺=565.3.

Example 1122-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0605] (112a) 2-Butylamino-5-trifluoromethylbenzoic acid (preparedanalogously to Example 103 with butyl iodide) was incorporated intoExample 104, step (104b), to give the title benzamide (25 mg). MS found:(M+H)⁺=597.2.

Example 1132-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0606] (113a) 4-(Methylthio)benzoic (22 mg) was incorporated intoExample 112 to give the title benzamide (25 mg). MS found: (M+H)⁺=565.3.

Example 1142-((Ethylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0607] (114a)[(Cis)-2-[[[[(2-(tert-butyloxycarbonylamino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamic acid benzyl ester (Example 97c) (1.4 g) was dissolved in 4MHCl/dioxane. After stirring at rt for 3h, the reaction was concentrated.A portion of this residue (500 mg) was dissolved in MeOH (5 mL) prior tothe addition of 10% Pd/C. A hydrogen balloon was added and the solutionwas stirred for 3 h. The palladium was filtered and the solution wasconcentrated. The resulting residue was cooled to 0° C. prior to theaddition of 4-methylmorpholine (0.55 mL) and 4-(methylthio)benzoic acid(168 mg). BOP Reagent (531 mg) was added, and the mixture was stirred atrt for 18 h. The DMF was removed. EtOAc was added along with 1 N HClsolution. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution, andbrine. The EtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave2-(amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide (360 mg). MS found: (M+H)⁺=509.2.

[0608] (114b)2-(amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide (Example 114a) (50 mg) was dissolved in THF (2.5 mL) prior tothe addition of triethylamine (30 mg) and ethyl isocyanate (21 mg).After stirring for 72 h, EtOAc was added along with 1 N HCl solution.The EtOAc layer was washed with 1 N HCl and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) provided the title benzamide(10 mg). MS found: (M+Na)⁺=602.4.

Example 1152-((Allylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0609] (115a) Allyl isocyanate (25 mg) was incorporated into Example114, step (114b), to give the title benzamide (10 mg). MS found:(M+H)⁺=592.3.

Example 1162-((2-methylpropyl)aminocarbonyl)amino-5-trifluoromethylbenzoic Acid

[0610] (116a) 2-Amino-5-trifluoromethylbenzoic acid (3.75 g) wasdissolved in DMF (20 mL) prior to the addition of K₂CO₃ (3.78 g) andallyl bromide (2.4 mL). After 3 h, the solution was diluted with EtOAcand was washed with brine solution and water. The organic layer wasdried (MgSO₄), filtered, and concentrated. Flash chromatography of theresulting residue gave the allyl ester as a yellow oil (2.6 g). Thisester was dissolved in THF (6 mL) and added dropwise to a THF (3.5 mL)solution of trichloromethyl chloroformate (1.1 mL). After stirring for18 h, the solution was concentrated. A portion (1.4 g) of the resultingresidue was dissolved in THF (2.2 mL) prior to the addition ofiso-butylamine (0.95 mL) in THF (3 mL). After 4 h, the solution wasdiluted with EtOAc and was washed with brine solution and 1N HCl. Theorganic layer was dried (MgSO₄), filtered, and concentrated to a whitesolid. This solid was dissolved in CH₃CN (30 mL) prior to the additionof pyrrolidine (0.23 mL) and Pd(PPh)₄ (64 mg). After 3 h, the solutionwas diluted with EtOAc and was washed 1N HCl. The organic layer wasdried (MgSO₄), filtered, and concentrated to2-((2-methylpropyl)aminocarbonyl)amino-5-trifluoromethylbenzoic acid(386 mg) as a white solid. MS found: (2M−H)⁻=607.3.

Example 1172-((Iso-butylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0611] (117a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine (6g) was dissolved in DMF (100 mL). After cooling to 0° C.,4-methylmorpholine (15.4 mL) and p-(methylthio)benzoic acid (5.2 g) wereadded. BOP Reagent (15.0 g) was added, and the mixture was stirred at rtfor 18 h. The DMF was removed. EtOAc was added along with 1 N HClsolution. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution, andbrine. The EtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave tert-butyl(cis)-2-{[4-(methylthio)benzoyl]amino}cyclohexylcarbamate (8.4 g). MSfound: (2M+Na)⁺=751.3.

[0612] (117b) The material, 117a, from above (8.4 g) was dissloved in 4MHCl/dioxane. After 3 h, the solution was concentrated. The resultingresidue was dissolved in DMF (50 mL). After cooling to 0° C.,4-methylmorpholine (12.6 mL) and N-Boc-glycine (4.8 g) were added. BOPReagent (15.3 g) was added, and the mixture was stirred at rt for 18 h.The DMF was removed. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave tert-butyl2-[((cis)-2-{[4-(methylthio)benzoyl]amino}cyclohexyl)amino]-2-oxoethylcarbamate (9.4 g). MS found: (M+Na)⁺=444.4.

[0613] (117c) A portion (2.3 g) of the material, (117b), from above wasdissloved in 4M HCl/dioxane. After 3 h, the solution was concentrated. Aportion of the resulting material (100 mg) was dissolved in DMF (5 mL).After cooling to 0° C., 4-methylmorpholine (0.15 mL) was added followedby 2-((2-methylpropyl)aminocarbonyl)amino-5-trifluoromethylbenzoic acid(Example 116) (26 mg). After 5 min, BOP Reagent (161 mg) was added andthe mixture was stirred at rt for 18 h. The DMF was removed. EtOAc wasadded along with 1 N HCl solution. The EtOAc layer was washed with 1 NHCl, NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄), filtered,and concentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (50 mg). MS found:(M+H)⁺=608.3.

Example 1182-((Cyclopentylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0614] (118a) 2-(cyclopentylaminocarbonyl)amino-5-trifluoromethylbenzoicacid (made analogously to Example 116 with cyclopentylamine in place ofiso-butylamine) (88.6 mg) was incorporated into Example 117, step(117c), to give the title benzamide (50 mg). MS found: (M+H)⁺=620.3.

Example 1192-((Tert-butoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0615] (119a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid(Takagishi et al., Synlett 1992, 360) (88.6 mg) was incorporated intoExample 117, step (117c), to give the title benzamide (25 mg). MS found:(M+H)⁺=609.3.

Example 1202-((Iso-propoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0616] (120a) 2-(Iso-propoxycarbonyl)amino-5-trifluoromethylbenzoic acid(98 mg) was incorporated into Example 117, step (117c), to give thetitle benzamide (20 mg). MS found: (M+H)⁺=595.3.

Example 1212-((Ethoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0617] (121a) 2-(Ethoxycarbonyl)amino-5-trifluoromethylbenzoic acid (96mg) was incorporated into Example 117, step (117c), to give the titlebenzamide (30 mg). MS found: (M+H)⁺=581.3.

Example 122N-[2-[(1-Pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine

[0618] (122a) 2-(Pyrrolidinylcarbonyl)amino-5-trifluoromethylbenzoicacid (made analogously to Example 116 with pyrrolidine in place ofiso-butylamine (2.9 g) was dissolved in DMF (40 mL). After cooling to 0°C., 4-methylmorpholine (3.2 mL) and glycine benzyl ester hydrogenchloride (5.6 g) were added. After 5 min, BOP Reagent (5.6 g) was addedand the mixture was stirred at rt for 18 h. EtOAc was added along with 1N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated to a solid (2.6 g). This solid was dissolved in MeOH (14mL) prior to the addition of 10% Pd/C. A hydrogen balloon was added andthe solution was stirred for 1 h. The palladium was filtered and thesolution was concentrated to give the title glycine derivative (2.0 g)as a white solid. MS found: (M+H)⁺=360.2.

Example 1232-((Pyrrolidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0619] (123a) Tert-butyl(cis)-2-{[4-(methylthio)benzoyl]amino]cyclohexylcarbamate (117a) wasdissolved in CH₂Cl₂ (5 mL) and cooled to 0° C. TFA (5 mL) was added andthe solution was stirred. After 1 h, the solution was concentrated. Aportion of the resulting residue (80 mg) was dissolved in DMF (2 mL).After cooling to 0° C., 4-methylmorpholine (0.1 mL) andN-[2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(Example 122)(75 mg) were added. After 5 min, BOP Reagent (116 mg) wasadded and the mixture was stirred at rt for 18 h. EtOAc was added alongwith 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (30 mg). MS found:(M+H)⁺=606.5.

Example 1242-((Morpholinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0620] (124a)N-[2-[(1-Morpholinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(made analogously to Example 122 with2-(morpholinylcarbonyl)amino-5-trifluoromethylbenzoic acid, see Example116) (78 mg) was incorporated into Example 123 to give the titlebenzamide (30 mg). MS found: (M+Na)⁺=644.6.

Example 1252-((Azetidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylBenzamide

[0621] (125a)N-[2-[(1-Azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(made analogously to Example 122 with2-(azetidinylcarbonyl)amino-5-trifluoromethylbenzoic acid, see Example116) (72 mg) was incorporated into Example 123 to give the titlebenzamide (35 mg). MS found: (M+H)⁺=592.5.

Example 126 Tert-butyl(cis)-3-({N-[2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycyl}amino)tetrahydro-2H-pyran-4-ylcarbamate

[0622] (126a) 3,4-Epoxytetrahydropyran (Tetrahedron 1974, 4013) (1 g)was dissolved in MeOH (10 mL) prior to the addition of NaN₃ (3.9 g) andNH₄Cl (3.2 g) in water (1 mL). The mixture was heated at 85° C. for 18h. After cooling, the solution was concentrated prior to the addition ofCH₂Cl₂ (100 mL). The solids were filtered away and the filtrate wasconcentrated. The resulting residue was dissolved in EtOAc (10 mL)followed by the addition of Boc₂O (3 g) and 20% Pd(OH)₂ (500 mg). Ahydrogen balloon was added and the mixture was stirred for 2 h. EtOAcwas added and the solution was filtered before concentration. Flashchromatography of the resulting residue gavetrans-4-(tert-butoxycarbonyl)aminotetrahydro-2H-pyran-3-ol (see also J.Med. Chem. 2001, 725) (900 mg). MS found: (M+H)⁺=218.1.

[0623] (126b) The pyran-3-ol (900 mg) from above, Example 126a, wasdissolved in CH₂Cl₂ and prior to the addition of triethylamine (1.73mL). After cooling to 0° C., methanesulfonyl chloride (0.48 mL) wasadded dropwise. The solution was stirred for 2 h before 1N HCl wasadded.

[0624] The organic layer was washed with 1 N HCl, NaHCO₃ solution, andbrine. The organic layer was dried (MgSO₄), filtered, and concentrated.The resulting residue was dissolved in DMSO (10 mL) prior to theaddition of NaN₃ (1.3 g). The solution was heated at 85° C. for 18 h.After cooling, EtOAc and water were added. The water layer was extractedwith EtOAc. The EtOAc was washed with brine, dried, and concentrated.Flash chromatography of the resulting residue gavecis-3-azido-4-(tert-butoxycarbonyl)aminotetrahydro-2H-pyran (430 mg),which was taken forward. This solid was dissolved in MeOH (10 mL) priorto the addition of 10% Pd/C (300 mg). A hydrogen balloon was added andthe solution was stirred for 1 h. The palladium was filtered and thesolution was concentrated. A portion of the resulting residue (50 mg)was dissolved in DMF (2 mL). After cooling to 0° C., 4-methylmorpholine(0.13 mL) andN-[2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(Example 122)(91 mg) were added. After 5 min, BOP Reagent (132 mg) wasadded and the mixture was stirred at rt for 18 h. EtOAc was added alongwith 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue gave thetitle compound (140 mg). MS found: (M+Na)⁺=580.5.

Example 1272-{[1-Pyrrolidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0625] (127a) The carbamate (140 mg) from above, Example 126, wasdissolved in CH₂Cl₂ (10 mL) and TFA (10 mL). After 0.5 h, the solutionwas concentrated. A portion (50 mg) of this residue was dissolved in THF(2 mL) prior to the addition of acetic acid (0.5 mL) and4-(methylthio)benzaldehyde (20 mg). After 30 min, NaHB(OAc)₃ (27 mg) wasadded and the solution was stirred for 2 h. The solution was filteredand reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (7 mg). MS found:(M+H)⁺=594.5.

Example 128 Tert-butyl(cis)-3-({N-[2-[(1-azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycyl}amino)tetrahydro-2H-pyran-4-ylcarbamate

[0626] (128a)N-[2-[(1-Azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(made analogously to Example 122 with2-(azetidinylcarbonyl)amino-5-trifluoromethylbenzoic acid, see Example116) (209.3 mg) was incorporated into Example 126 to give the titlecarbamate (123.7 mg). MS found: (M+Na)⁺=566.4.

Example 1292-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0627] (129a) The carbamate (80 mg), Example 128, from above wasincorporated into Example 127 to give the title benzamide (11 mg). MSfound: (M+H)⁺=580.5.

Example 1302-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methoxy)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0628] (130a) Anisaldehyde (43 mg) was incorporated into Example 129 togive the title benzamide (36 mg). MS found: (M+H)⁺=564.4.

Example 1311-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane

[0629] (131a)(Cis)-N-benzyl-2,2,2-trifluoro-N-(7-oxa-bicyclo[4.1.0]hept-3-yl)acetamide (M. Chini et al., J. Org. Chem. 1990, 55, 4265-4272) (3.7 g)was dissolved in methanol (50 mL) prior to addition of NaN₃ (1.6 g) inH₂O (5 mL). The flask was fitted with a condenser and heated at refluxfor 2 h. The cooled solution was partitioned between EtOAc and water andthe organic layer was washed with NaHCO₃ and brine. The organic layerwas dried, filtered, and concentrated. Flash chromatography of theresulting residue providedN-(3-azido-4-hydroxycyclohexyl)-N-benzyl-2,2,2-trifluoroacetamide (3.1g). MS found: (M+Na)⁺=378.2.

[0630] (131b) A portion of the above derivative (131a) (3.1 g) wasdissolved in THF (20 mL) prior to addition of PPh₃ (3.6 g). The solutionwas stirred at rt for 12 h and water (5 mL) was added. The solution wasstirred for an additional 12 h, and partitioned between EtOAc and water.The water layer was treated with 2 N NaOH until the pH=9 and wasextracted EtOAc (3×). The combined organic extracts were dried, filteredand concentrated. The residue was partially purified by flashchromatography and was dissolved in THF (160 mL) and water (40 mL). Thesolution was treated with NaHCO₃ (3 g) prior to addition ofdi-tert-butyl dicarbonate (4.7 g). The solution was stirred for 8 h,partitioned between EtOAc and water, and the organic layer was washedwith NaHCO₃ and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the residue provided{5-[benzyl-(2,2,2-trifluoroacetyl)amino]-2-hydroxycyclohexyl} carbamicacid tert-butyl ester (3.1 g). MS found: (M+Na)⁺=439.1.

[0631] (131c) The above derivative (131b) (3.1 g) was dissolved inmethanol (100 mL) prior to addition of KOH (3 g), dissolved in water (50mL). The flask was fitted with a condenser and heated at reflux for 2 h.The cooled solution was partitioned between EtOAc and water. The waterlayer was extracted with EtOAc (3×). The combined organic extracts weredried, filtered, and concentrated. The residue was dissolved in methanol(100 mL) prior to addition of 5% Pd/C (0.5 g). This reaction was placedon a Parr apparatus at 50 psi hydrogen pressure. After shaking for 8 h,the Pd/C was filtered off and the solution was concentrated. The residuewas dissolved in THF (80 mL) and water (20 mL). The solution was treatedwith NaHCO₃ (1.7 g) prior to addition of benzyl chloroformate (1.3 mL).The solution was stirred for 8 h, and partitioned between EtOAc andwater. The organic layer was washed with NaHCO₃ and brine. The organiclayer was dried, filtered, and concentrated. Flash chromatography of theresidue provided(3-tert-butoxycarbonylamino-4-hydroxycyclohexyl)carbamic acid benzylester (2.75 g). MS found: (M+Na)⁺=387.2.

[0632] (131d) A stirred solution of PPh₃ (2.3 g) was dissolved in THF(20 mL) and cooled to 0° C. prior to the dropwise addition of DEAD (1.4mL). The solution was stirred for 0.5 h and combined with a solution ofthe above derivative (131c) (1.6 g) in THF (10 mL) and 10% HN₃ inbenzene (10.5 mL). The solution was stirred for 4 h and partitionedbetween EtOAc and water. The organic layer was washed with NaHCO₃ andbrine. The organic layer was dried, filtered, and concentrated. Flashchromatography of the residue provided(2-azido-5-benzyloxycarbonylaminocyclohexyl)carbamic acid tert-butylester (1.6 g). MS found: (M+Na)⁺=412.2.

[0633] (131e) The above derivative (131d) (1.5 g) was dissolved in THF(50 mL) prior to addition of PPh₃ (1.5 g). The solution was stirred atrt for 12 h and water (5 mL) was added. The solution was stirred for 12h and partitioned between EtOAc and water. The water layer was treatedwith 2 N NaOH until the pH=9 and was extracted with EtOAc (3×). Thecombined organic extracts were dried, filtered, and concentrated. Flashchromatography of the residue provided(2-amino-5-benzyloxycarbonylaminocyclohexyl)carbamic acid tert-butylester (1.1 g). MS found: (M+H)⁺=364.2.

[0634] (131f) A portion of the above derivative (131e) (150 mg) wasdissolved in DMF (2 mL) prior to addition of Hunig's base (0.5 mL).4-(thiomethyl)benzoic acid (140 mg) was added followed by HATU (470 mg).The solution was stirred for 8 h then quenched with aqueous NH₄Cl. Themixture was partitioned between EtOAc and water. The organic layer waswashed with NaHCO₃, 5% LiCl (3×), and brine. The organic layer wasdried, filtered, and concentrated. Flash chromatography of the residueprovided[3-tert-butoxycarbonylamino-4-(4-methylthio-benzoylamino)cyclohexyl]carbamic acid benzyl ester (198 mg). MS found: (M+H)⁺=514.2.

[0635] (131g) A portion of the above derivative (131f) (198 mg) wasdissolved in CH₂Cl₂ (10 mL) prior to addition of TFA (10 mL). Thesolution was stirred for 4 h, and concentrated. The residue wasdissolved in DMF (2 mL) prior to addition of Hunig's base (0.5 mL).(2-tert-Butoxycarbonylamino-5-trifluoromethylbenzoylamino)acetic acid(181 mg) was added followed by HATU (470 mg). The solution was stirredfor 8 h and quenched with aqueous NH₄Cl. The mixture was partitionedbetween EtOAc and water. The organic layer was washed with NaHCO₃, 5%LiCl (3×), and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the residue provided[2-({[5-benzyloxycarbonylamino-2-(4-methylthio-benzoylamino)cyclohexylcarbamoyl]-methyl}carbamoyl)-4-trifluoromethylphenyl]carbamic acid tert-butyl ester (250 mg). MS found: (M+H)⁺=758.1.

[0636] (131h) A portion of the above derivative (131g) (250 mg) wasdissolved in HOAc (3 mL) prior to addition of 38% HBr (3 mL). Thesolution was stirred for 12 h and poured into NaHCO₃ (100 mL). Thesolution was adjusted to pH=9 with 2 N NaOH and extracted with EtOAc.The organic layer was dried, filtered, and concentrated. Flashchromatography of the residue provided the title compound (120 mg). MSfound: (M+H)⁺=524.3.

Example 132{4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane

[0637] (132a) (3-Trifluoromethylbenzoylamino) acetic acid (77 mg) wasincorporated into Example 131, step (131g). Flash chromatography of theresidue provided{4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid benzyl ester (47 mg). MS found: (M+H)⁺=643.2.

[0638] (132b) A portion of the above derivative (132a) (16 mg) wasincorporated into Example 131, step (131h). Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the residueprovided the title compound (8 mg). MS found: (M+H)⁺=509.2.

Example 1331-(4-Methanesulfonylbenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl-4-aminocyclohexane

[0639] (133a) A portion of the above derivative (132a) (51 mg) wasdissolved in CH₂Cl₂ (20 mL) prior to addition of K₂CO₃ (138 mg) and 50%m-CPBA (86 mg). The mixture was stirred for 8 h and quenched withaqueous sodium thiosulfate. The organic layer was washed with NaHCO₃ andbrine. The organic layer was dried, filtered, and concentrated. Theresidue was dissolved in CH₂Cl₂ (10 mL) prior to addition of TFA (10mL). The solution was stirred for 4 h and concentrated. The residue wasdissolved in DMF (2 mL) prior to addition of Hunig's base (0.2 mL).(3-trifluoromethylbenzoylamino)acetic acid (77 mg) was added followed byHATU (150 mg). The solution was stirred for 8 h, and quenched withaqueous NH₄Cl. The mixture was partitioned between EtOAc and water. Theorganic layer was washed with NaHCO₃, 5% LiCl (3×), and brine. Theorganic layer was dried, filtered, and concentrated. Flashchromatography of the residue provided{4-(4-Methanesulfonylbenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid benzyl ester (41 mg). MS found: (M+H)⁺=675.2.

[0640] (133b) A portion of the above derivative (133a) (35 mg) wasincorporated into Example 131, step (131h). Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the residueprovided the title compound (14 mg). MS found: (M+H)⁺=541.2.

Example 1341-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)cyclohexane

[0641] (134a) A portion of the above derivative (131h) (35 mg) wasdissolved in methanol (0.5 mL) prior to addition of HC(OCH₃)₃ (2 mL) andacetone (0.2 mL). The solution was stirred for 1 h and NaBH(OAc)₃ (100mg) was added. The solution was stirred for 12 h and poured into NaHCO₃(10 mL). The solution was adjusted to pH=9 with 2 N NaOH and extractedwith EtOAc. The organic layer was dried, filtered, and concentrated.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (14mg). MS found: (M+H)⁺=566.1.

Example 1351-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(3-methylureido)cyclohexane

[0642] (135a) A portion of the above derivative (131h) (35 mg) wasdissolved in CH₂Cl₂ (5 mL) prior to addition of Hunig's base (0.2 mL).Methyl isocyanate (40 mg) was added and the solution was stirred for 4h. The solution was poured into NaHCO₃ (10 mL) and EtOAc 20 mL). Theorganic layer was dried, filtered and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the residueprovided the title compound (10 mg). MS found: (M+H)⁺=581.0.

Example 1361-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-aminocyclohexane

[0643] (136a) A portion of the above derivative (131e) (100 mg) wasdissolved in DMF (2 mL) prior to addition of Hunig's base (0.3 mL).(3-trifluoromethyl-benzoylamino)-acetic acid (136 mg) was added followedby HATU (310 mg). The solution was stirred for 8 h and quenched withNH₄Cl. The mixture was partitioned between EtOAc and water. The organiclayer was washed with NaHCO₃, 5% LiCl (3×), and brine. The organic layerwas dried, filtered and concentrated. Flash chromatography of theresidue provided{5-benzyloxycarbonylamino-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid tert-butyl ester (140 mg). MS found: (M+H)⁺=593.3.

[0644] (136b) A portion of the above derivative (136a) (136 mg) wasdissolved in CH₂Cl₂ (10 mL) prior to addition of TFA (10 mL). Thesolution was stirred for 4 h, and concentrated. The residue wasdissolved in DMF (2 mL) prior to addition of Hunig's base (0.3 mL).4-(thiomethyl)benzoic acid (77 mg) was added followed by HATU (262 mg).The solution was stirred for 8 h and quenched with aqueous NH₄Cl. Themixture was partitioned between EtOAc and water. The organic layer waswashed with NaHCO₃, 5% LiCl (3×), and brine. The organic layer wasdried, filtered, and concentrated. Flash chromatography of the residueprovided{3-(4-methylthiobenzoylamino)-4-[2-(3-trifluoromethylbenzoylamino)acetylamino]cyclohexyl}carbamicacid benzyl ester (56 mg). MS found: (M+H)⁺=643.3.

[0645] (136c) A portion of the above derivative (136b) (31 mg) wasincorporated into Example 131, step (131h). Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the residueprovided the title compound (22 mg). MS found: (M+H)⁺=509.2.

Example 1371-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-(2-propylamino)cyclohexane

[0646] (137a) A portion of the above derivative (136c) (15 mg) wasincorporated into Example 134, step (134a). Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the residueprovided the title compound (13 mg). MS found: (M+H)⁺=551.0.

Example 1381-(4-Methylthio-benzoylamino)-2-[2-(2-Amino-5-trifluoromethyl-benzoylamino)-acetylamino]-4-aminocyclohexane

[0647] (138a)(Cis)-N-benzyl-2,2,2-trifluoro-N-(7-oxa-bicyclo[4.1.0]hept-3-yl)acetamide(M. Chini et al., J. Org. Chem. 1990, 55, 4265-4272) (1.2 g) wasincorporated into Example 131, step (131a). The residue was purified byflash chromatography to provideN-(4-azido-3-hydroxycyclohexyl)-N-benzyl-2,2,2-trifluoroacetamide (785mg). MS found: (M+Na)⁺=378.2.

[0648] (138b) A portion of the above derivative (138a) (785 mg) wasincorporated into Example 131, step (131b). The residue was purified byflash chromatography to provide14-[benzyl-(2,2,2-trifluoroacetyl)-amino]-2-hydroxycyclohexyl}carbamicacid tert-butyl ester (765 mg). MS found: (M−H)-=415.0.

[0649] (138c) A portion of the above derivative (138b) (765 mg) wasincorporated into Example 131, step (131c). The residue was purified byflash chromatography to provide(4-tert-butoxycarbonylamino-3-hydroxycyclohexyl)carbamic acid benzylester (580 mg). MS found: (M+H)⁺=365.2.

[0650] (138d) A portion of the above derivative (138c) (530 mg) wasincorporated into Example 131, step (131d). The residue was purified byflash chromatography to provide(2-azido-4-benzyloxycarbonylaminocyclohexyl)carbamic acid tert-butylester (480 mg). MS found: (M+Na)⁺=412.2.

[0651] (138e) A portion of the above derivative (138d) (380 mg) wasincorporated into Example 131, step (131e). The residue was purified byflash chromatography to provide(3-amino-4-tert-butoxycarbonylaminocyclohexyl)carbamic acid benzyl ester(320 mg). MS found: (M+H)⁺=364.2.

[0652] (138f) The above derivative (138e) (80 mg) was incorporated intoExample 131, step (131g). Flash chromatography of the residue provided{4-benzyloxycarbonylamino-2-[2-(2-tert-butoxycarbonylamino-5-trifluoromethylbenzoylamino)acetylamino]cyclohexyl}carbamicacid tert-butyl ester (97 mg). MS found: (M−H)—-706.4.

[0653] (138g) The derivative (138f) (97 mg) was incorporated intoExample 136, step (136b). Flash chromatography of the residue provided[3-[2-(2-amino-5-trifluoromethyl-benzoylamino)acetylamino]-4-(4-methylsulfanylbenzoylamino)cyclohexyl]carbamicacid benzyl ester (80 mg). MS found: (M+H)⁺=658.2.

[0654] (138h) The derivative (138g) (60 mg) was incorporated intoExample 131, step (131h). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (16 mg). MS found: (M+H)⁺=524.3.

Example 1394-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-aminocyclohexane

[0655] (139a) A portion of the above derivative (138e) (50 mg)incorporated into Example 136, step (136b). The organic layer was dried,filtered, and concentrated. Flash chromatography of the residue provided{4-benzyloxycarbonylamino-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl}carbamicacid tert-butyl ester (74 mg). MS found: (M+H)⁺=593.3.

[0656] (139b) A portion of the derivative (139a) (70 mg) wasincorporated into Example 136, step (136b) Reverse phase HPLCpurification (gradient elution) of the residue provided4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid benzyl ester (20 mg). MS found: (M+H)⁺=643.2.

[0657] (139c) A portion of the above derivative (139b) (60 mg) wasincorporated into Example 131, step (131h). Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the residueprovided the title compound (28 mg). MS found: (M+H)⁺=509.3.

Example 1404-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)-cyclohexane

[0658] (140a) The derivative (139c) (15 mg) was incorporated intoExample 134, step (134a). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (11 mg). MS found: (M+H)⁺=551.2.

Example 1411-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-5-aminocyclohexane

[0659] (141a) The derivative (138e) (35 mg) was incorporated intoExample 131, step (131f). Flash chromatography of the residue provided[4-benzyloxycarbonylamino-2-(4-methylthiobenzoylamino)cyclohexyl]carbamicacid tert-butyl ester (44 mg). MS found: (M+H)⁺=514.2.

[0660] (141b) The above derivative (141a) (40 mg) was incorporated intoExample 132, step (132a). The residue was triturated with EtOAc andcollected on a sintered glass frit to provide the title compound{3-(4-methylthiobenzoylamino)-4-[2-(3-trifluoromethylbenzoylamino)acetylamino]cyclohexyl}carbamic acid benzyl ester (43 mg). MS found:(M+H)⁺=643.3.

[0661] (141c) The above derivative (141b) (40 mg) was incorporated intoExample 131, step (131h). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (15 mg). MS found: (M+H)⁺=509.1.

Example 143 [2-Isopropylamino-5-(trifluoromethyl)]benzoic acid

[0662] (143a) Isopropylamine (4.0 mL) was dissolved in THF (20 mL). Thissolution was cooled to 0° C. and n-butyllithium (2.5 M, 20 mL) wasadded. The reaction was stirred for 90 min, then transferred to asolution of [2-fluoro-5-(trifluoromethyl)]benzoic acid (4.2 g) in THF(40 mL) at −78° C. This mixture was stirred for 15 min and the reactionwas quenched with aqueous NH₄Cl. The mixture was extracted with EtOAc(3×). The organic layer was dried, filtered, and concentrated. Flashchromatography of the resulting residue provided the title compound (2.4g). MS found: (M+H)⁺=248.2.

Example 1442-Isopropylamino-N-{[(cis)₂-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide

[0663] (144a) N-tert-Butyloxycarbonylcyclohexane-(cis)-1,2-diamine (518mg) was dissolved in CH₂Cl₂ (45 mL) and DMF (15 mL) prior to theaddition of Hunig's base (1.7 mL) and([2-(isopropylamino)-5-(trifluoromethyl)benzoylamino]acetic acid(incorporated Example 143 into Example 122) (400 mg) and HATU (1.84 g)at rt. The reaction was stirred for 8 h and quenched with water. Theorganic layer was washed with 1 N HCl, aqueous NaHCO₃, 5% aqueous LiCl,and brine. The organic layer was dried, filtered, and concentrated.Flash chromatography of the residue providedcis-{2-[2-(2-isopropylamino-5-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl}carbamicacid tert-butyl ester (534 mg). MS found: (M−Boc+H)⁺=401.1.

[0664] (144b) The above derivative (144a) (150 mg) was dissolved inCH₂Cl₂ (12 mL) and cooled to 0° C. Trifluoroacetic acid (4 mL) was addedand the reaction was warmed to rt, stirred for 1 h and concentrated. Theresidue was dissolved in CH₂C¹ ₂, washed with aqueous NH₄OH, andconcentrated. The residue was dissolved in trimethylorthoformate (3 mL)prior to the addition of 4-methylsulfanylbenzyaldehyde (400 uL). After 6h, NaBH₄ (113 mg) was added. The reaction was stirred for 12 h, quenchedwith water and extracted with CH₂Cl₂ (3×). The CH₂Cl₂ layer was washedwith aqueous NH₄Cl and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the residue provided2-isopropylamino-N-{[(cis)₂-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide(114 mg). MS found: (M+H)⁺=537.2.

Example 1452-(3-Isopropylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide

[0665] (145a)[2-(3-Isopropylureido)-5-trifluoromethylbenzoylamino]acetic acid wasincorporated into Example 144, step (144a) to give(2-(cis)-[2-[2-(3-isopropylureido)-5-trifluoromethylbenzoylamino]acetylamino]cyclohexyl)carbamic acid tert-butyl ester (404 mg). MS found: (M−Boc+H)⁺=444.0.

[0666] (145b) The above derivative (145a) was incorporated into Example144, step (144b). Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (75mg). MS found: (M+H)⁺=580.1.

Example 1462-(3-Morpholinylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide

[0667] (146a){2-[(Morpholinylcarbonyl)amino]-5-trifluoromethylbenzoylamino} aceticacid was incorporated into Example 144, step (144a) to providecis-[2-(2-{2-[(morpholine-4-carbonyl)-amino]-5-trifluoromethylbenzoylamino}acetylamino)cyclohexyl]carbamic acid tert-butyl ester (606 mg). MS found: (M−Boc+H)⁺=472.0.

[0668] (146b) The above derivative (146a) was incorporated into Example144, step (144b). Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (58 mg). MS found: (M+H)⁺=608.

Example 1512-amino-N-{2-[((3S,4R)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0669] (151a) 1-Tert-butoxycarbonyl-4-azido-3-hydroxy-piperidine(Marquis et al. J. Med. Chem. 2001, 44, 725) (39.6 g) was dissolved inMeOH (500 mL) prior to the addition of 10% Pd/C (10 g) in a Parr bottle.The reaction was shaken at 50 psi overnight. The reaction was filteredand the volatiles were removed under reduced pressure. The resultingresidue (35.4 g) was dissolved in THF (1000 mL) and water (240 mL) alongwith Et₃N (68.6 mL) and (Cbz)₂O (52 g). The reaction was stirred atambient temperature overnight and the volatiles were removed underreduced pressure. The resulting material was taken into ether and washedwith 10% aqueous citric acid, water, saturated aqueous sodiumbicarbonate, brine, dried over MgSO₄, and the volatiles were removedunder reduced pressure. Flash chromatography of the resulting residuegave1-tert-butoxycarbonyl-4-(benzyloxycarbonyl)amino-3-hydroxy-piperidine(37.2 g) as the faster eluting isomer 1e. MS found: (M+Na)⁺=534.5.

[0670] (151b) To a stirred, cooled (5° C. water bath) solution of 2.81grams of triphenylphosphine in 80 mL of benzene was added 1.82 mL ofDEAD dropwise over 5 minutes. After stirring 15 minutes at 5° C. apremixed solution of 3 grams of 151a (from above) in 40 mL THF and 80 mLof ˜2.3 molar HN₃ in benzene was added over 20 minutes. The reaction wasstirred at ambient temperature overnight. Ether was added and themixture was washed with saturated aqueous sodium bicarbonate, water,brine and dried over MgSO₄. The volatiles were removed under reducedpressure. The resulting material (combined from two runs) was dissolvedin THF (400 mL) and triphenylphosphine (13.5 g) was added along with 4mL of water. The reaction was stirred at 65° C. for 14 hours and thevolatiles were removed under reduced pressure. The material was takeninto ether and extracted 4 times with 0.1M aqueous HCl. The combinedaqueous layers were washed twice with ether and made basic (pH>9) by theaddition of sodium bicarbonate. The resulting slurry was extracted threetimes with ether, dried over MgSO₄ and the volatiles were removed underreduced pressure affording 3 grams of1-tert-butoxycarbonyl-3-amino-4-(benzyloxycarbonyl)amino-piperidine. MSfound: (M+H)⁺=350.4.

[0671] (151c) The above material (151b, 2.0 g) was dissolved in DMF (40mL) prior to the addition of NMM (1.9 mL),N-[2-[(1-t-butoxycarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine (seeExample 122) (2.3 g), and HATU (2.3 g). After stirring overnight atambient temperature the volatiles were removed under reduced pressureand resulting material was slurried in ether and washed with 10% aqueouscitric acid, water, saturated aqueous sodium bicarbonate, brine, driedover MgSO₄, and the volatiles were removed under reduced pressure. Thisresulted in tert-butyl(cis)-4-{[(benzyloxy)carbonyl]amino}-3-{[1-{[2-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)benzoyl]amino}2-oxoethyl]amino}-1-piperidinecarboxylate(4.05 g). MS found: (M+H)⁺=692.4.

[0672] (151d) The above material (151c) (13.4 g) was dissolved in CH₂Cl₂(50 mL) and TFA (50 mL). After stirring for 30 minutes, the volatileswere removed under reduced pressure. The resulting residue was dissolvedin CH₃CN (200 mL) prior to the addition of potassium carbonate (10.7 g)and allylbromide (1.83 mL). The reaction was stirred at ambienttemperature overnight, the mixture was filtered and the volatiles wereremoved under reduced pressure. The material was dissolved in ether andwashed with water, saturated aqueous brine, dried over MgSO₄. Thevolatiles were removed under reduced pressure affording benzyl(cis)-1-allyl-3-{[1-{[2-amino-5-(trifluoromethyl)benzoyl]amino}2-oxoethyl]amino}-4-piperidinylcarbamate(8 g). MS found: (M+H)⁺=534.5.

[0673] (151e) The above material (151d) (8.0 g) was dissolved in MeOH(100 mL) prior to the addition of 10% Pd/C (8 g). This was stirred underhydrogen (balloon) for 6 hours. The mixture was filtered and thevolatiles removed under reduced pressure. The resulting residue wasdissolved in MeOH (250 mL) prior to the addition of4-methylthiobenzaldehyde (1.78 mL), sodium cyanoborohydride (2.0 g), andzinc chloride (4.4 g). The reaction was stirred at ambient temperatureovernight. The volatiles were removed under reduced pressure andresulting material was partitioned in ether and water. The ether phasewas washed with water, then extracted 4× with 0.1N HCl. All the acidicextracts were combined and washed twice with ether, rendered basic(pH>8.5) by the addition of sodium bicarbonate, extracted three timeswith dichloromethane, dried over MgSO₄, and the volatiles were removedunder reduced pressure. The resulting material was chromatographed onsilica gel eluting with a gradient of 2-5% methanol/chloroform affording1.8 grams as the mixture of enantiomers. The mixture was chromatographedon a chiracel OD column eluting with 15% ethanol/hexane. The fasterenantiomer was collected, the volatiles were removed under reducedpressure and the resulting material was lypholized from a mixture ofwater/TFA affording the title benzamide (0.98 g). MS found:(M+H)⁺=538.5.

Example 1522-Amino-N-{2-[((3R,4S)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0674] (152a) The final chiracel OD column from above also gave thisenantiomer (second) as the title compound. MS found: (M+H)⁺=538.5.

Example 1532-amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0675] (153a) MeI (0.58 mL of 0.10 g/mL solution in CH₃CN) wasincorporated into Example 151d to give benzyl(cis)-1-methyl-3-{[1-{[2-amino-5-(trifluoromethyl)benzoyl]amino}2-oxoethyl]amino}-4-piperidinylcarbamate(107 mg). LRMS found (M+H)⁺=508.3.

[0676] (153b) The above material (153 a) (100 mg) was dissolved in MeOH(5 mL) prior to the addition of 10% Pd/C (100 mg). This was stirredunder hydrogen (balloon) for 2 hours. The mixture was filtered and thevolatiles removed under reduced pressure. The resulting residue wasdissolved in DMF (1.5 mL) prior to the addition of NMM (0.032 mL),4-methylthiobenzoic acid (0.018 g), and HATU (0.038 g). After stirringovernight at ambient temperature the volatiles were removed underreduced pressure. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (29mg). MS found: (M+H)⁺=524.4.

Example 154N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0677] (154a) (3-Trifluoromethylbenzoylamino) acetic acid and4-chlorobenzaldehyde were incorporated into Example 151 (without theallyl bromide alkylation of step 151d) to give the title benzamide. MSfound: (M+H)⁺=469.3.

Example 155N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0678] (155a) (3-Trifluoromethylbenzoylamino) acetic acid and4-methylthiobenzaldehyde were incorporated into Example 151 (without theallyl bromide alkylation of step 151d) to give the title benzamide. MSfound: (M+H)⁺=481.2.

Example 1562-Amino-N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0679] (156a) 4-Chlorobenzaldehyde was incorporated into Example 151(without the allyl bromide alkylation of step 151d) to give the titlebenzamide. MS found: (M+H)⁺=484.4.

Example 1572-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0680] (157a) 4-Methylthiobenzaldehyde was incorporated into Example 151(without the allyl bromide alkylation of step 151d) to give the titlebenzamide. MS found: (M+H)⁺=496.5.

Example 1582-Amino-N-{2-[((cis)-4-{[4-ethylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0681] (158a) 4-Ethylthiobenzaldehyde was incorporated into Example 151(without the allyl bromide alkylation of step 151d) to give the titlebenzamide. MS found: (M+H)⁺=510.5.

Example 159N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0682] (159a) MeI and (3-Trifluoromethylbenzoylamino) acetic acid wereincorporated into Example 151 to give the title benzamide. MS found:(M+H)⁺=493.3.

Example 160N-{2-[((cis)-4-{bis[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0683] (160a) The final reverse phase HPLC purification from theprocedure above (159a) also gave the title benzamide. MS found:(M+H)⁺=631.3.

Example 1612-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0684] (161a) MeI and was incorporated into Example 151 to give thetitle benzamide. MS found: (M+H)⁺=510.3.

Example 162N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0685] (162a) (3-Trifluoromethylbenzoylamino) acetic acid (substitutedin step 151c) and acetyl chloride/Et₃N (substituted for allylbromide/K₂CO₃, step 151d) were incorporated into Example 151 to give thetitle benzamide. MS found: (M+H)⁺=551.4.

Example 1632-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0686] (163a) Crotyl bromide and was incorporated into Example 151 togive the title benzamide. MS found: (M+H)⁺=552.5.

Example 1642-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0687] (164a) N-[2-[cyclohexylamino]-5-(trifluoromethyl)benzoyl]glycine(see Example 143 with cyclohexyl amine and Example 122) was incorporatedinto Example 151 to give the title benzamide. MS found: (M+H)⁺=620.6.

Example 1652-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0688] (165a) N-[2-[Iso-propylamino]-5-(trifluoromethyl)benzoyl]glycine(see Example 143 and Example 122) was incorporated into Example 151 togive the title benzamide. MS found: (M+H)⁺=580.5.

Example 1662-(Pyrrolidinylcarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0689] (166a) 2-(Pyrrolidinylcarbonyl)amino-5-trifluoromethylbenzoicacid (see Example 122) was incorporated into Example 151 to give thetitle benzamide. MS found: (M+H)⁺=635.6.

Example 1672-(Methylaminocarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0690] (167a) 2-(Methylcarbonyl)amino-5-trifluoromethylbenzoic acid (seeExample 122) was incorporated into Example 151 to give the titlebenzamide. MS found: (M+H)⁺=595.6.

Example 1683-Amino-N-[2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0691] (168a) 3-Amino-5-trifluoromethylbenzoic acid (see Example 122)was incorporated into Example 151 to give the title benzamide. MS found:(M+H)⁺=538.5.

Example 169N-{2-[((cis)-4-{[4-aminosulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0692] (169a) 4-Aminosulfonylbenzoic acid (into step 153b) and(3-trifluoromethylbenzoylamino) acetic acid (into step 151c) wereincorporated into Example 151 without step 151d (skip this step) to givethe title benzamide. MS found: (M+H)⁺=528.3.

Example 170N-{2-[((cis)-4-{[4-methylsulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0693] (170a) 4-Methylsulfonylbenzoic acid was incorporated into Example169 to give the title benzamide. MS found: (M+H)⁺=527.0.

Example 1712-Amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0694] (171a)N-[2-[(1-t-butoxycarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine wasincorporated into Example 153 and step 151d was skipped to give thetitle benzamide. MS found: (M+H)⁺=510.3.

Example 172N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0695] (172a) (3-Trifluoromethylbenzoylamino) acetic acid wasincorporated into Example 153 (by way of 151c) to give the titlebenzamide. MS found: (M+H)⁺=509.3.

Example 173N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0696] (173a) Acetyl chloride/Et₃N was incorporated into Example 172(via step 153a) to give the title benzamide. MS found: (M+H)⁺=559.3.

Example 1742-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0697] (174a) Crotyl bromide was incorporated into Example 153 (via step153a) to give the title benzamide. MS found: (M+H)⁺=566.5.

Example 1752-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0698] (175a) N-[2-[cyclohexylamino]-5-(trifluoromethyl)benzoyl]glycine(see Example 143 with cyclohexyl amine and Example 122) and allylbromide were incorporated into Example 153 to give the title benzamide.MS found: (M+H)⁺=634.6.

Example 1762-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0699] (176a) N-[2-[iso-propylamino]-5-(trifluoromethyl)benzoyl]glycine(see Example 143 with i-propylamine and Example 122) and allyl bromidewere incorporated into Example 153 to give the title benzamide. MSfound: (M+H)⁺=594.4.

Example 1773-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

[0700] (177a) N-[3-(amino)-5-(trifluoromethyl)benzoyl]glycine (seeExample 122) and allyl bromide were incorporated into Example 153 togive the title benzamide. MS found: (M+H)⁺=552.4.

Example 178N-{2-[((cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

[0701] (178a)1-tert-butoxycarbonyl-3-amino-4-(benzyloxycarbonyl)amino-piperidine(151b) (300 mg) was dissolved in DMF (5 mL) prior to addition of Hunig'sbase (0.45 mL). 4-(aminosulfonyl)benzoic acid (210 mg) was addedfollowed by BOP (420 mg). The solution was stirred for 8 h then quenchedwith aqueous NH₄Cl. The mixture was partitioned between EtOAc and water.The organic layer was washed with NaHCO₃, 5% LiCl (3×), and brine. Theorganic layer was dried, filtered, and concentrated. Flashchromatography of the residue provided tert-butyl(cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-{[(benzyloxy)carbonyl]amino}-1-piperidinecarboxylate(210 mg). MS found: (M−H)⁻=531.3.

[0702] (178b) The material from above (178a) (200 mg) was dissolved inCH₂Cl₂ (2 mL) prior to the addition of Pd(OAc)₂ (28 mg), Et₃SiH (0.29mL), and Et₃N (0.02 mL). The solution was stirred overnight. This wasquench with saturated NaHCO₃ and extracted with CH₂Cl₂. The organiclayer was dried, filtered, and concentrated. The resulting residue wasdissolved in DMF (1 mL) prior to addition of NMM (0.032 mL),(3-Trifluoromethylbenzoylamino) acetic acid (see Example 122) (29 mg),and HATU (42 mg). After stirring overnight at ambient temperature thevolatiles were removed under reduced pressure and EtOAc was added. Thiswas washed with 10% aqueous citric acid, water, saturated aqueous sodiumbicarbonate, brine, dried over MgSO₄, and the volatiles were removedunder reduced. This material was dissolved in CH₂Cl₂ (1 mL) prior to theaddition of TFA (1 mL). After 1 h, the solution was concentrated.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamide. MS found: (M+H)⁺=528.1.

Example 179N-{[4-Dimethylamino-2-(4-methylsulfanyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

[0703] (179a) Cis-4-(benzyloxy)-1,2-epoxycyclohexane (6 g) (Chini et al.J. Org. Chem. 1990, 55, 4265) was dissolved in MeOH (160 mL) prior tothe addition of NaN₃ (9.5 g) and NH₄Cl (3.4 g) in water (20 mL). Themixture was heated at 85° C. for 18 h. After cooling, the solution wasconcentrated prior to the addition of CH₂Cl₂. The solids were filteredaway and the filtrate was concentrated. A portion (500 mg) of theresulting residue was dissolved in EtOAc (10 mL) followed by theaddition of Boc₂O (485 mg) and 20% Pd(OH)₂ (200 mg). A hydrogen balloonwas added and the mixture was stirred for 2 h. EtOAc was added and thesolution was filtered before concentration. This material was dissolvedin CH₂Cl₂ (5 mL) and cooled to 0° C. prior to the addition of Et₃N (0.26mL) and methanesulfonyl chloride (0.3 mL). After 2 h, the CH₂Cl₂ wasremoved and EtOAc was added. This was washed with 1N HCl, saturatedNaHCO₃, and brine. The organic layer was dried, filtered, andconcentrated. This solid was dissolved in DMSO (5 mL) prior to theaddition of NaN₃ (326 mg). This was heated at 80° C. for 18 h. Aftercooling to 0° C., water was added and it was extracted with EtOAc. Theorganic layer was washed with brine, dried, filtered, and concentrated.Flash chromatography of the resulting residue gave(2-azido-5-benzyloxy-cyclohexyl)-carbamic acid tert-butyl ester (250mg). MS found: (M+H)⁺=347.2.

[0704] (179b) The above material (3 g) was dissolved in MeOH (25 mL)prior to the addition of 10% Pd/C (2 g). A hydrogen balloon was addedand the solution was stirred for 1.0 h. The palladium was filtered andthe solution was concentrated. This material was dissolved in DMF priorto the addition of 4-methylmorpholine (6.7 mL) and3-trifluoromethyl-benzoylamino)-acetic acid (3.3 g). After cooling to 0°C., BOP Reagent (7 g) was added. The resulting mixture was warmed to rtand was stirred overnight. EtOAc was added along with 1 N HCl solution(aq). The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution (aq), andbrine. The EtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave{5-benzyloxy-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamicacid tert-butyl ester (8 g). MS found: (M+Na)⁺=550.4.

[0705] (179c) The above material (6 g) was dissolved in MeOH (50 mL)prior to the addition of 10% Pd(OH)₂ (2.5 g). Hydrogen gas (50 psi) wasadded and the solution was shaken overnight. The palladium was filteredand the solution was concentrated (4.75 g). A portion (300 mg) of thismaterial was dissolved in CH₂Cl₂ (5 mL) and cooled to 0° C. prior to theaddition of Et₃N (0.26 mL) and methanesulfonyl chloride (0.08 mL). After1 h, the CH₂Cl₂ was removed and EtOAc was added. This was washed with 1NHCl, saturated NaHCO₃, and brine. The organic layer was dried, filtered,and concentrated. This solid was dissolved in DMSO (5 mL) prior to theaddition of NaN₃ (211 mg). This was heated at 80° C. for 18 h. Aftercooling to 0° C., water was added and it was extracted with EtOAc. Theorganic layer was washed with brine, dried, filtered, and concentrated.Flash chromatography of the resulting residue gave{5-azido-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamicacid tert-butyl ester (140 mg). MS found: (M+H)⁺=485.5.

[0706] (179d) The above material (135 mg) was dissolved in MeOH (5 mL)prior to the addition of 10% Pd/C (100 mg). A hydrogen balloon was addedand the solution was stirred 1 h. The palladium was filtered and thesolution was concentrated. This was dissolved in MeOH (5 mL) prior tothe addition of 37% formaldehyde (106 mg) solution (aq). After 10 min,NaBH₃CN (49 mg) was added. The reaction was stirred for 2 h before thesolution was-concentrated. EtOAc was added along with some water. Theorganic layer was dried, filtered, and concentrated. This was dissolvedin CH₂Cl₂ (5 mL) and TFA (5 mL). After 1 h, it was concentrated. Thiswas dissolved in THF (2.5 mL) prior to the addition of4-(methylthio)benzaldehyde (0.04 mL) and Hunig's base (0.1 mL). After 10min, NaHB(OAc)₃ was added. The reaction was stirred for 2 h before thesolution was filtered and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) of the resulting residue gavethe title compound (35 mg). MS found: (M+H)⁺=523.4.

Example 180N-{[2-(4-Chloro-benzylamino)-4-dimethylamino-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

[0707] (180a) 4-Chlorobenzaldehyde (17 mg) was incorporated into Example179 to give the title compound (2.5 mg). MS found: (M+H)⁺=511.3.

Example 181N-{[4-Dimethylamino-2-(4-methoxy-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

[0708] (181a) 4-(Methoxy)benzaldehyde (0.01 mL) was incorporated intoExample 179 to give the title compound (3.5 mg). MS found: (M+H)⁺=507.4.

Example 182N-{[4-Dimethylamino-2-(4-methyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

[0709] (182a) 4-(Methyl)benzaldehyde (0.01 mL) was incorporated intoExample 179 to give the title compound (4.5 mg). MS found: (M+H)⁺=491.4.

[0710] Table 1 contains representative examples of the presentinvention. Each of the following structural formulas are to be used inthe indicated example (Ex) range paired with the given R¹ and R²substituent. TABLE 1

MS Ex R¹ R² [M + H] 1 4-chlorophenyl 3-trifluoromethylphenyl 468.2 22,4-dimethylphenyl 3-trifluoromethylphenyl 462.3 3 2,4,6-trimethylphenyl3-trifluoromethylphenyl 476.4 4 4-benzyloxyphenyl3-trifluoromethylphenyl 540.4 5 2,4-difluorophenyl3-trifluoromethylphenyl 470.3 6 2-chloro-4-fluorophenyl3-trifluoromethylphenyl 486.2 7 4-fluoro-2-trifluoromethylphenyl3-trifluoromethylphenyl 520.2 8 2,4-dichlorophenyl3-trilfuoromethylphenyl 502.1 9 2-fluoro-6-trifluoromethylphenyl3-trifluoromethylphenyl 520.2 10 2-chloro-5-trifluoromethylphenyl3-trifluoromethylphenyl 536.2 11 1-naphthyl 3-trifluoromethylphenyl484.3 12 3-furyl 3-trifluoromethylphenyl 504.3 13 2,4-dimethylphenyl3-trifluoromethylphenyl 476.3 14 4-chlorophenyl 3-trifluoromethylphenyl482.3 15 2,4-dimethylphenyl 3-trifluoromethylphenyl 462.4 164-chlorophenyl 3-trifluoromethylphenyl 468.3 17 4-nitrophenyl3-trifluoromethylphenyl 479.3 18 4-isopropylphenyl3-trifluoromethylphenyl 476.3 19 4-trifluoromethylphenyl3-trifluoromethylphenyl 502.3 20 4-trifluoromethoxyphenyl3-trifluoromethylphenyl 518.2 21 4-phenoxyphenyl 3-trifluoromethylphenyl526.2 22 1-naphthyl 3-trifluoromethylphenyl 484.3 23 2-naphthyl3-trifluoromethylphenyl 484.3 24 3-indolyl 3-trifluoromethylphenyl 473.325 4-chlorophenyl 3-trifluoromethylphenyl 482.2 26 3-furyl3-trifluoromethylphenyl 504.3 27 4-chlorophenyl 3-trifluoromethylphenyl468.2 28 4-methylthiophenyl 3-trifluoromethylphenyl 480.2 294-methylsulfonylphenyl 3-trifluoromethylphenyl 512.1 30 4-iodophenyl3-trifluoromethylphenyl 431.0 31 4-aminosulfonyl 3-trifluoromethylphenyl535.1 phenyl M + Na 32 4-chlorophenyl 3-trifluoromethylphenyl 454.1 332,4-dimethylphenyl 3-trifluoromethylphenyl 448.2 34 4-methylphenyl3-trifluoromethylphenyl 434.1 35 4-chlorophenyl 3-trifluoromethylphenyl482.2 36 4-methylphenyl 3-trifluoromethylphenyl 484.2 M + Na 374-fluorophenyl 3-trifluoromethylphenyl 466.2 38 phenyl3-trifluoromethylphenyl 448.2 39 4-bromophenyl 3-trifluoromethylphenyl528.1 40 4-phenoxyphenyl 3-trifluoromethylphenyl 540.2 414-trifluoromethyl 3-trifluoromethylphenyl 516.2 phenyl 425-benzotriazolyl 3-trifluoromethylphenyl 489.2 43 4-iodophenyl3-trifluoromethylphenyl 574.2 44 4-cyanophenyl 3-trifluoromethylphenyl473.3 45 4-trifluoromethoxy 3-trifluoromethylphenyl 532.2 phenyl 464-formylphenyl 3-trifluoromethylphenyl 476.3 47 4-carbomethoxy3-trifluoromethylphenyl 506.2 phenyl 48 4-nitrophenyl3-trifluoromethylphenyl 493.2 49 4-aminophenyl 3-trifluoromethylphenyl463.2 50 4-methoxyphenyl 3-trifluoromethylphenyl 478.3 514-methylthiophenyl 3-trifluoromethylphenyl 494.2 52 4-methylsulfonyl3-trifluoromethylphenyl 526.2 phenyl 53 4-aminosulfonyl3-trifluoromethylphenyl 527.2 phenyl 54 4-isopropylphenyl3-trifluoromethylphenyl 490.3 55 4-phenylthiophenyl3-trifluoromethylphenyl 556.2 56 N,N-diethylsulfamoyl3-trifluoromethylphenyl 583.3 phenyl 57 4-trifluoromethyl3-trifluoromethylphenyl 548.2 thiophenyl 58 4-chlorophenyl3-trifluoromethylphenyl 550.1 59 3,4-dimethylphenyl3-trifluoromethylphenyl 420.1 60 4-methylphenyl 3-trifluoromethylphenyl406.1 61 4-aminosulfonyl 2-amino-5-iodophenyl 622.2 phenyl M + Na 624-aminosulfonyl 2-amino-5-chlorophenyl 530.3 phenyl M + Na 634-aminosulfonyl 3-chlorophenyl 515.2 phenyl 64 4-aminosulfonyl3-trifluoromethoxyphenyl 543.1 phenyl 65 4-aminosulfonyl2-(t-butoxycarbonyl)amino-5-tri- 664.3 phenyl fluoromethylphenyl M + Na66 4-aminosulfonyl 2-amino-5-tri- 564.2 phenyl fluoromethylphenyl M + Na67 4-aminosulfonyl 2-trifluoromethylphenyl 564.3 phenyl M + Na 684-aminosulfonyl 3-chlorophenyl 530.1 phenyl 69 4-aminosulfonyl2-(ethylcarbonyl)amino-5-iodo- 670.9 phenyl phenyl M − H 704-aminosulfonyl 2-(methylcarbonyl)amino-5-iodo- 656.9 phenyl phenyl M −H 71 4-aminosulfonyl N-methyl-2-(t-butoxy- 678.2 phenylcarbonyl)amino-5-tri- M + Na fluoromethylphenyl 72 4-aminosulfonyl2-(ethylcarbonyl)amino-5-tri- 636.1 phenyl fluoromethylphenyl M + Na 734-aminosulfonyl 2-(benzylamino)-5-tri- 654.2 phenyl fluoromethylphenylM + Na 74 4-aminosulfonyl 2-(ethylamino)-5-tri- 592.1 phenylfluoromethylphenyl M + Na 75 4-aminosulfonyl 2-(methylamino)-5-tri-578.2 phenyl fluoromethylphenyl M + Na 76 4-aminosulfonyl2-amino-5-bromophenyl 554.1 phenyl M + H 77 4-aminosulfonyl2-(t-butoxycarbonyl)amino-5-tri- 680.2 phenyl fluoromethoxyphenyl M + Na78 4-aminosulfonyl 2-amino-5-tri- 580.1 phenyl fluoromethoxyphenyl M +Na 79 4-aminosulfonyl 2-(allylamino)-5-tri- 604.1 phenylfluoromethylphenyl M + Na 80 4-aminosulfonyl 2-((2-methyl-2-pro- 618.1phenyl penyl)amino)-5-tri- M + Na fluoromethylphenyl 81 4-aminosulfonyl2-(cyclo- 618.2 phenyl propylmethylene)amino-5-tri- M + Nafluoromethylphenyl 82 4-aminosulfonyl 2-(butlamino)-5-tri- 620.1 phenylfluoromethylphenyl M + Na 83 4-aminosulfonyl 2-(propylamino)-5-tri-606.2 phenyl fluoromethylphenyl M + Na 84 4-aminosulfonyl2-((2-methyl-2-pro- 620.2 phenyl pyl)amino)-5-tri- M + Nafluoromethylphenyl 85 4-aminosulfonyl 2-(aminocarbonyl)amino-5-iodo-665.1 phenyl phenyl M + Na 86 4-aminosulfonyl 2-acetylamino-5-iodophenyl642.1 phenyl M + H 87 4-aminosulfonyl 2-(methylamino)-5-iodo- 614.1phenyl phenyl M + H 88 4-aminosulfonyl 2-(ethylamino)-5-iodophenyl 628.1phenyl M + H 89 4-aminosulfonyl 2-trifluoroacetylamino-5-iodo- 696.1phenyl phenyl M + H 90 4-aminosulfonyl 2-amino-5-nitrophenyl 519.1phenyl M + H 91 4-aminosulfonyl 2-(iso- 708.1 phenylpropoxycarbonyl)amino-5-iodo- M + Na phenyl 92 4-aminosulfonyl 2-(tert-722.1 phenyl butoxycarbonyl)amino-5-iodo- M + Na phenyl 934-aminosulfonyl 2-amino-3,5-dinitrophenyl 632.0 phenyl M + H 944-aminosulfonyl 2-(iso- 649.2 phenyl propylaminocarbonyl)amino-5-tri-M + Na fluoromethylphenyl 95 4-aminosulfonyl 2-(cyclo- 652.2 phenylhexylcarbonyl)amino-5-tri- M + H fluoromethylphenyl 96 4-aminosulfonyl2-(cyclo- 652.2 phenyl pentylmethylenecarbonyl)amino-5-tri- M + Hfluoromethylphenyl 97 4-methylsulfonyl 2-(cyclo- 651.2 phenylhexylcarbonyl)amino-5-tri- M + H fluoromethylphenyl 98 4-(methylthio)2-(cyclo- 619.3 phenyl hexylcarbonyl)amino-5-tri- M + Hfluoromethylphenyl 99 4-(methylthio) 2-(iso- 594.3 phenylpropylaminocarbonyl)amino-5-tri- M + H fluoromethylphenyl 100 4-(methyl-2-(iso- 626.2 sulfonyl) propylaminocarbonyl)amino-5-tri- M + H phenylfluoromethylphenyl 101 4-aminosulfonyl 2-(methylsulfonyl)amino-5-tri-620.1 phenyl fluoromethylphenyl M + H 102 4-aminosulfonyl2-(aminocarbonyl)amino-5-tri- 585.2 phenyl fluoromethylphenyl M + H 1044-(methyl- 2-(allyl)amino-5-tri- 581.3 sulfonyl) fluoromethylphenyl M +H phenyl 105 4-(methylthio) 2-(allyl)amino-5-tri- 549.3 phenylfluoromethylphenyl M + H 106 4-(methyl- 2-(2-methyl-2-pro- 595.2sulfonyl) penyl)amino-5-tri- M + H phenyl fluoromethylphenyl 1074-(methylthio) 2-(2-methyl-2-pro- 563.3 phenyl penyl)amino-5-tri- M + Hfluoromethylphenyl 108 4-(methyl- 2-(propyl)amino-5-tri- 583.3 sulfonyl)fluoromethylphenyl M + H phenyl 109 4-(methylthio)2-(propyl)amino-5-tri- 551.3 phenyl fluoromethyphenyl M + H 1104-(methyl- 2-(2-methylpropyl)amino-5-tri- 597.3 sulfonyl)fluoromethylphenyl M + H phenyl 111 4-(methylthio)2-(2-methylpropyl)amino-5-tri- 565.3 phenyl fluoromethylphenyl M + H 1124-(methyl- 2-(butyl)amino-5-tri- 597.2 sulfonyl) fluoromethylphenyl M +H phenyl 113 4-(methylthio) 2-(butyl)amino-5-tri- 565.3 phenylfluoromethylphenyl M + H 114 4-(methylthio) 2-(ethyl- 602.4 phenylaminocarbonyl)amino-5-tri- M + Na fluoromethylphenyl 115 4-(methylthio)2-(allyl- 592.3 phenyl aminocarbonyl)amino-5-tri- M + Hfluoromethylphenyl 117 4-(methylthio) 2-(iso- 608.3 phenylbutylaminocarbonyl)amino-5-tri- M + H fluoromethylphenyl 1184-(methylthio) 2-(cyclo- 620.3 phenyl pentylaminocarbonyl)a- M + Hmino-5-tri- fluoromethylphenyl 119 4-(methylthio) 2-(tert- 609.3 phenylbutoxycarbonyl)amino-5-tri- M + H fluoromethylphenyl 120 4-(methylthio)2-(iso- 595.3 phenyl propoxycarbonyl)amino-5-tri- M + Hfluoromethylphenyl 121 4-(methylthio) 2-(Ethoxycarbonyl)amino-5-tri-581.3 phenyl fluoromethylphenyl M + H 123 4-(methylthio) 2-(pyr- 606.5phenyl rolidinylcarbonyl)amino-5-tri- M + H fluoromethylphenyl 1244-(methylthio) 2-(morpho- 644.6 phenyl linylcarbonyl)amino-5-tri- M + Nafluoromethylphenyl 125 4-(methylthio) 2-(aze- 592.5 phenyltidinylcarbonyl)amino-5-tri- M + H fluoromethylphenyl 127 4-(methylthio)2-(pyr- 594.5 phenyl rolidinylcarbonyl)amino-5-tri- M + Hfluoromethylphenyl 129 4-(methylthio) 2-(aze- 580.5 phenyltidinylcarbonyl)amino-5-tri- M + H fluoromethylphenyl 1304-(methoxy)phenyl 2-(azetidinyl- 564.4 carbonyl)amino-5-tri- M + Hfluoromethylphenyl 131 4-(methylthio) 2-amino-5-tri- 524.3 phenylfluoromethylphenyl M + H 131g 4-(methylthio)2-(t-butoxycarbonyl)amino-5-tri- 758.1 phenyl fluoromethylphenyl M + H132 4-(methylthio) 3-trifluoromethylphenyl 509.2 phenyl M + H 132a4-(methylthio) 3-trifluoromethylphenyl 643.2 phenyl M + H 133 4-(methyl-3-trifluoromethylphenyl 541.2 sulfonyl) M + H phenyl 133a 4-(methyl-3-trifluoromethylphenyl 675.2 sulfonyl) M + H phenyl 134 4-(methylthio)2-amino-5-tri- 566.1 phenyl fluoromethylphenyl M + H 135 4-(methylthio)2-amino-5-tri- 581.0 phenyl fluoromethylphenyl M + H 136 4-(methylthio)3-trifluoromethylphenyl 509.2 phenyl M + H 137 4-(methylthio)3-trifluoromethylphenyl 551.0 phenyl M + H 138 4-(methylthio)2-amino-5-tri- 524.3 phenyl fluoromethylphenyl M + H 140 4-(methylthio)3-trifluoromethylphenyl 551.2 phenyl M + H 141 4-(methylthio)3-trifluoromethylphenyl 509.1 phenyl M + H 144 4-(methylthio)2-(iso-propyl)amino-5-tri- 537.2 phenyl fluoromethylphenyl M + H 1454-(methylthio) 2-(i-propyl- 580.1 phenyl aminocarbonyl)amino-5-tri- M +H fluoromethylphenyl 146 4-(methylthio) 2-(morpho- 608 phenyllinylcarbonyl)amino-5-tri- M + H fluoromethylphenyl 151 4-(methylthio)2-amino-5-tri- 538.5 phenyl fluoromethylphenyl M + H 152 4-(methylthio)2-amino-5-tri- 538.5 phenyl fluoromethylphenyl M + H 153 4-(methylthio)2-amino-5-tri- 524.4 phenyl fluoromethylphenyl M + H 154 4-chlorophenyl3-trifluoromethylphenyl 469.3 M + H 155 4-(methylthio)3-trifluoromethylphenyl 481.2 phenyl M + H 156 4-chlorophenyl2-amino-5-tri- 484.4 fluoromethylphenyl M + H 157 4-(methylthio)2-amino-5-tri- 496.5 phenyl fluoromethylphenyl M + H 158 4-(ethyl-2-amino-5-tri- 510.5 thio)phenyl fluoromethylphenyl M + H 1594-(methylthio) 3-trifluoromethylphenyl 493.3 phenyl M + H 1604-(methylthio) 3-trifluoromethylphenyl 631.3 phenyl M + H 1614-(methylthio) 2-amino-5-tri- 510.3 phenyl fluoromethylphenyl M + H 1624-(methylthio) 3-trifluoromethylphenyl 551.4 phenyl M + H 1634-(methylthio) 2-amino-5-tri- 552.5 phenyl fluoromethylphenyl M + H 1644-(methylthio) 2-(cyclohexyl)amino-5-tri- 620.6 phenylfluoromethylphenyl M + H 165 4-(methylthio) 2-(iso-propyl)amino-5-tri-580.5 phenyl fluoromethylphenyl M + H 166 4-(methylthio) 2-(pyr- 635.6phenyl rolidinylcarbonyl)amino-5-tri- M + H fluoromethylphenyl 1674-(methylthio) 2-(methyl- 595.6 phenyl aminocarbonyl)amino-5-tri- M + Hfluoromethylphenyl 168 4-(methylthio) 3-amino-5-tri- 538.5 phenylfluoromethylphenyl M + H 169 4-aminosulfonyl 3-trifluoromethylphenyl528.3 phenyl M + H 170 4-methylsuflonyl 3-trifluoromethylphenyl 527.0phenyl M + H 171 4-(methylthio) 2-amino-5-tri- 510.3 phenylfluoromethylphenyl M + H 172 4-(methylthio) 3-trifluoromethylphenyl509.3 phenyl M + H 173 4-(methylthio) 3-trifluoromethylphenyl 559.3phenyl M + H 174 4-(methylthio) 2-amino-5-tri- 566.5 phenylfluoromethylphenyl M + H 175 4-(methylthio) 2-(cyclohexyl)amino-5-tri-634.6 phenyl fluoromethylphenyl M + H 176 4-(methylthio)2-(iso-propyl)amino-5-tri- 594.4 phenyl fluoromethylphenyl M + H 1774-(methylthio) 3-amino-5-tri- 552.4 phenyl fluoromethylphenyl M + H 1784-aminosulfonyl 3-trifluoromethylphenyl 528.1 phenyl M + H 1794-(methylthio)phenyl 3-trifluoromethylphenyl 523.4 M + H 1804-(chloro)phenyl 3-trifluoromethylphenyl 511.3 M + H 1814-(methoxy)phenyl 3-trifluoromethylphenyl 507.4 M + H 1824-(methyl)phenyl 3-trifluoromethylphenyl 491.4 M + H

[0711] TABLE 2 Table 2 contains additional examples of the presentinvention. Each of the following structural formulas (A to GG) are to bematched with each R¹ and each R² independently.

R¹ 1 4-chlorophenyl 2 4-bromophenyl 3 4-iodophenyl 4 4-ethenylphenyl 54-ethylphenyl 6 4-ethynylphenyl 7 4-isopropylphenyl 8 4-phenoxyphenyl 94-trifluoromethylphenyl 10 4-cyanophenyl 11 4-nitrophenyl 124-methylphenyl 13 4-methylthiophenyl 14 4-methylsulfonylphenyl 154-methoxyphenyl 16 2,4-dimethylphenyl 17 2,4,6-trimethylphenyl 183,4-dimethylphenyl 19 4-fluorophenyl 20 1-naphthyl 21 2-naphthyl 224-chloro-3-methylphenyl 23 2,4-dichlorophenyl 24 2,5-dimethylphenyl 252-chloro-5-tri- fluoromethylphenyl 26 4-chloro-2-methylphenyl 274-chloro-2-fluorophenyl 28 2,4-difluorophenyl 29 2-chloro-4-tri-fluoromethylphenyl 30 2-fluoro-6-tri- fluoromethylphenyl 312-chloro-5-tri- fluoromethylphenyl 32 4-fluoro-2-tri- fluoromethylphenyl33 4-hydroxyphenyl 34 3-indolyl 35 3,5-dimethyl-4-isoxazole 363,5-dimethyl-1-phenyl-4-py- razolyl 37 3-amino-4-methylphenyl 383-amino-4-chlorophenyl 39 3-amino-4-methoxyphenyl R² 13-trifluoromethylphenyl 2 3-bromophenyl 3 3,5-dibromophenyl 43-chlorophenyl 5 3-trifluoromethoxyphenyl 6 3-trifluorothiophenyl 73-cyanophenyl 8 3-iodophenyl 9 3-formylphenyl 10 3-nitrophenyl 115-tert-butyl-2-furanyl 12 3-methylsulfonylphenyl 132-amino-5-chlorophenyl 14 2-amino-5-bromophenyl 15 2-amino-5-iodophenyl16 2-amino-5-trifluoromethylphenyl 17 2-amino-5-fluorophenyl 182-amino-5-trifluoromethoxyphenyl 19 2-amino-5-cyanophenyl 202-amino-5-formylphenyl 21 2-(methylamino)-5-chlorophenyl 222-(methylamino)-5-bromophenyl 23 2-(methylamino)-5-iodophenyl 242-(methylamino)-5-fluorophenyl 252-(methylamino)-5-trifluoromethylphenyl 262-(methylamino)-5-trifluoromethoxyphenyl 272-(methylamino)-5-cyanophenyl 28 2-(ethylamino)-5-chlorophenyl 292-(ethylamino)-5-bromophenyl 30 2-(ethylamino)-5-iodophenyl 312-(methylamino)-5-fluorophenyl 32 2-(ethylamino)-5-trifluoromethylphenyl33 2-(methylamino)-5-trifluoromethoxyphenyl 342-(ethylamino)-5-cyanophenyl 35 2-(aminocarbonyl)amino-5-chlorophenyl 362-(aminocarbonyl)amino-5-bromophenyl 372-(aminocarbonyl)amino-5-iodophenyl 382-(aminocarbonyl)amino-5-fluorophenyl 392-(aminocarbonyl)amino-5-trifluoromethylphenyl 402-(aminocarbonyl)amino-5-trifluoromethyloxyphenyl 412-(aminocarbonyl)amino-5-cyanophenyl 422-[(methylamino)carbonyl)]amino-5-chlorophenyl 432-[(methylamino)carbonyl)]amino-5-bromophenyl 442-[(methylamino)carbonyl)]amino-5-iodophenyl 452-[(methylamino)carbonyl)]amino-5-fluorophenyl 462-[(methylamino)carbonyl)]amino-5-tri- fluoromethylphenyl 472-[(methylamino)carbonyl)]amino-5-tri- fluoromethoxyphenyl 482-[(methylamino)carbonyl)]amino-5-cyanophenyl R⁴ 1 H 2 methyl 3 ethyl 4propyl 5 i-propyl 6 Butyl 7 i-butyl 8 t-butyl 9 Pentyl 10 Hexyl 11C(O)methyl 12 C(O)H 13 C(O)methyl 14 C(O)ethyl 15 C(O)propyl 16C(O)i-propyl 17 C(O)butyl 18 C(O)i-butyl 19 C(O)t-butyl 20 C(O)pentyl 21C(O)cyclopropyl R^(5a) 1 H 2 methyl 3 ethyl 4 propyl 5 i-propyl 6 Butyl7 i-butyl 8 Pentyl 9 Hexyl 10 cyclopropyl 11 cyclobutyl

[0712] TABLE 3 Table 3 contains additional examples of the presentinvention. Each of the following structural formulas (A to W) are to bematched with each R¹ and each R² independently.

R¹ 1 4-chlorophenyl 2 4-bromophenyl 3 4-iodophenyl 4 4-ethenylphenyl 54-ethylphenyl 6 4-ethynylphenyl 7 4-isopropylphenyl 8 4-phenoxyphenyl 94-trifluoromethylphenyl 10 4-cyanophenyl 11 4-nitrophenyl 124-methylphenyl 13 4-methylthiophenyl 14 4-methylsulfonylphenyl 154-aminosulfonylphenyl 16 4-(methylamino)sulfonylphenyl 17 4-(di-methylamino)sulfonylphenyl 18 4-formylphenyl 194-(methoxycarbonyl)phenyl 20 4-trifluoromethoxyphenyl 21 4-aminophenyl22 4-methylthiophenyl 23 4-(aminocarbonyl)phenyl 24 4-aminophenyl 25phenyl 26 4-propylphenyl 27 4-difluoromethylphenyl 284-(phenylthio)phenyl 29 4-ethylthiophenyl 30 4-ethylsulfonylphenyl R² 13-trifluoromethylphenyl 2 3-bromophenyl 3 3,5-dibromophenyl 43-chlorophenyl 5 3-trifluoromethoxyphenyl 6 3-trifluoromethylthiophenyl7 3-cyanophenyl 8 3-iodophenyl 9 3-formylphenyl 10 3-nitrophenyl 115-tert-butyl-2-furanyl 12 3-methylsulfonylphenyl 132-amino-5-chlorophenyl 14 2-amino-5-bromophenyl 15 2-amino-5-iodophenyl16 2-amino-5-trifluoromethylphenyl 17 2-amino-5-fluorophenyl 182-amino-5-trifluoromethoxyphenyl 19 2-amino-5-cyanophenyl 202-amino-5-formylphenyl 21 2-(methylamino)-5-chlorophenyl 222-(methylamino)-5-bromophenyl 23 2-(methylamino)-5-iodophenyl 242-(methylamino)-5-fluorophenyl 252-(methylamino)-5-trifluoromethylphenyl 262-(methylamino)-5-trifluoromethoxyphenyl 272-(methylamino)-5-cyanophenyl 28 2-(ethylamino)-5-chlorophenyl 292-(ethylamino)-5-bromophenyl 30 2-(ethylamino)-5-iodophenyl 312-(methylamino)-5-fluorophenyl 32 2-(ethylamino)-5-trifluoromethylphenyl33 2-(methylamino)-5-trifluoromethoxyphenyl 342-(ethylamino)-5-cyanophenyl 35 2-(aminocarbonyl)amino-5-chlorophenyl 362-(aminocarbonyl)amino-5-bromophenyl 372-(aminocarbonyl)amino-5-iodophenyl 382-(aminocarbonyl)amino-5-fluorophenyl 392-(aminocarbonyl)amino-5-trifluoromethylphenyl 402-(aminocarbonyl)amino-5-trifluoromethyloxyphenyl 412-(aminocarbonyl)amino-5-cyanophenyl 422-[(methylamino)carbonyl)]amino-5-chlorophenyl 432-[(methylamino)carbonyl)]amino-5-bromophenyl 442-[(methylamino)carbonyl)]amino-5-iodophenyl 452-[(methylamino)carbonyl)]amino-5-fluorophenyl 462-[(methylamino)carbonyl)]amino-5-tri- fluoromethylphenyl 472-[(methylamino)carbonyl)]amino-5-tri- fluoromethoxyphenyl 482-[(methylamino)carbonyl)]amino-5-cyanophenyl R⁴ 1 H 2 methyl 3 ethyl 4propyl 5 i-propyl 6 Butyl 7 i-butyl 8 t-butyl 9 Pentyl 10 Hexyl 11C(O)methyl 12 C(O)H 13 C(O)methyl 14 C(O)ethyl 15 C(O)propyl 16C(O)i-propyl 17 C(O)butyl 18 C(O)i-butyl 19 C(O)t-butyl 20 C(O)pentyl 21C(O)cyclopropyl

Utility

[0713] Compounds of formula I are shown to be modulators of chemokinereceptor activity using assays know by those skilled in the art. In thissection, we describe these assays and give their literature reference.By displaying activity in these assays of MCP-1 antagonism, compounds offormula I are expected to be useful in the treatment of human diseasesassociated with chemokines and their cognate receptors. The definitionof activity in these assays is a compound demonstrating an IC₅₀ of 20 μMor lower in concentration when measured in a particular assay.

[0714] Antagonism of MCP-1 Binding to Human PBMC

[0715] (Yoshimura et al., J. Immunol. 1990, 145, 292)

[0716] Compounds of the present invention have activity in theantagonism of MCP-1 binding to human PBMC (human peripheral bloodmononuclear cells) described here.

[0717] Millipore filter plates (#MABVN1250) are treated with 100 μl ofbinding buffer (0.5% bovine serum albumin, 20 mM HEPES buffer and 5 mMmagnesium chloride in RPMI 1640 media) for thirty minutes at roomtemperature. To measure binding, 50 μl of binding buffer, with orwithout a known concentration compound, is combined with 50 μl of ¹²⁵-Ilabeled human MCP-1 (to give a final concentration of 150 μMradioligand) and 50 μl of binding buffer containing 5×10⁵ cells. Cellsused for such binding assays can include human peripheral bloodmononuclear cells isolated by Ficoll-Hypaque gradient centrifugation,human monocytes (Weiner et al., J. Immunol. Methods. 1980, 36, 89), orthe THP-1 cell line which expresses the endogenous receptor. The mixtureof compound, cells and radioligand are incubated at room temperature forthirty minutes. Plates are placed onto a vacuum manifold, vacuumapplied, and the plates washed three times with binding buffercontaining 0.5M NaCl. The plastic skirt is removed from the plate, theplate allowed to air dry, the wells punched out and counted. The percentinhibition of binding is calculated using the total counts obtained inthe absence of any competing compound and the background bindingdetermined by addition of 100 nM MCP-1 in place of the test compound.

[0718] Antagonism of MCP-1-Induced Calcium Influx

[0719] (Sullivan, et al. Methods Mol. Biol., 114, 125-133 (1999)

[0720] Compounds of the present invention have activity in theantagonism of MCP-1-induced calcium influx assay described here.

[0721] Calcium mobilization is measured using the fluorescent Ca²⁺indicator dye, Fluo-3. Cells are incubated at 8×10⁵ cells/ml inphosphate-buffered saline containing 0.1% bovine serum albumin, 20 mMHEPES buffer, 5 mM glucose, 1% fetal bovine serum, 4 μM Fluo-3 AM and2.5 mM probenecid for 60 minutes at 37° C. Cells used for such calciumassays can include human monocytes isolated as described by Weiner etal., J. Immunol. Methods, 36, 89-97 (1980) or cell lines which expressesthe endogenous CCR₂ receptor such as THP-1 and MonoMac-6. The cells arethen washed three times in phosphate-buffered saline containing 0.1%bovine serum albumin, 20 mM HEPES, 5 mM glucose and 2.5 mM probenecid.The cells are resuspended in phosphate-buffered saline containing 0.5%bovine serum albumin, 20 mM HEPES and 2.5 mM probenecid at a finalconcentration of 2-4×10⁶ cells/ml. Cells are plated into 96-well,black-wall microplates (100 μl/well) and the plates centrifuged at 200×gfor 5 minutes. Various concentrations of compound are added to the wells(50 μl/well) and after 5 minutes, 50 μl/well of MCP-1 is added to give afinal concentration of 10 nM. Calcium mobilization is detected by usinga fluorescent-imaging plate reader. The cell monolayer is excited withan argon laser (488 nM) and cell-associated fluorescence measured for 3minutes, (every second for the first 90 seconds and every 10 seconds forthe next 90 seconds). Data are generated as arbitrary fluorescence unitsand the change in fluorescence for each well determined as themaximum-minimum differential. Compound-dependent inhibition iscalculated relative to the response of MCP-1 alone.

[0722] Antagonism of MCP-1-induced Human PBMC Chemotaxis

[0723] (Bacon et al., Brit. J. Pharmacol. 1988, 95, 966)

[0724] Compounds of the present invention have activity in theantagonism of MCP-1-induced human PBMC chemotaxis assay described here.

[0725] Neuroprobe MBA96-96-well chemotaxis chamber, Polyfiltronics MPC96 well plate, and Neuroprobe polyvinylpyrrolidone-free polycarbonatePFD5 8-micron filters are warmed in a 37° C. incubator. Human PeripheralBlood Mononuclear Cells (PBMCs) (Boyum et al., Scand. J. Clin. LabInvest. Suppl. 1968, 97, 31), freshly isolated via the standard ficolldensity separation method, are suspended in DMEM at 1×10⁷ c/ml andwarmed at 37° C. A 60 nM solution of human MCP-1 is also warmed at 37°C. Dilutions of test compounds are made up at 2× the concentrationneeded in DMEM. The PBMC suspension and the 60 nm MCP-1 solution aremixed 1:1 in polypropylene tubes with prewarmed DMEM with or without adilution of the test compounds. These mixtures are warmed in a 37° C.tube warmer. To start the assay, add the MCP-1/compound mixture into thewells of the Polyfiltronics MPC 96 well plate that has been placed intothe bottom part of the Neuroprobe chemotaxis chamber. The approximatevolume is 400 μl to each well and there should be a positive meniscusafter dispensing. The 8 micron filter is placed gently on top of the 96well plate, a rubber gasket is attached to the bottom of the upperchamber, and the chamber is assembled. A 200 μl volume of the cellsuspension/compound mixture is added to the appropriate wells of theupper chamber. The upper chamber is covered with a plate sealer, and theassembled unit is placed in a 37° C. incubator for 45 minutes. Afterincubation, the plate sealer is removed and all the remaining cellsuspension is aspirated off. The chamber is disassembled and the filtergently removed. While holding the filter at a 90 degree angle,unmigrated cells are washed away using a gentle stream of phosphatebuffered saline and the top of the filter wiped with the tip of a rubbersqueegee. Repeat this wash twice more. The filter is air dried and thenimmersed completely in Wright Geimsa stain for 45 seconds. The filter isthen washed by soaking in distilled water for 7 minutes, and then a 15second additional wash in fresh distilled water. The filter is again airdried. Migrated cells on the filter are quantified by visual microscopy.Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

[0726] For example, an instant compound which inhibits one or morefunctions of a mammalian chemokine receptor (e.g., a human chemokinereceptor) may be administered to inhibit (i.e., reduce or prevent)inflammation or infectious disease. As a result, one or moreinflammatory process, such as leukocyte emigration, adhesion,chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatorymediator release, is inhibited.

[0727] Similarly, an instant compound which promotes one or morefunctions of the mammalian chemokine receptor (e.g., a human chemokine)as administered to stimulate (induce or enhance) an immune orinflammatory response, such as leukocyte emigration, adhesion,chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatorymediator release, resulting in the beneficial stimulation ofinflammatory processes. For example, eosinophils can be recruited tocombat parasitic infections. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for an instant compound which promotes one or morefunctions of the mammalian chemokine receptor if one contemplates thedelivery of sufficient compound to cause the loss of receptor expressionon cells through the induction of chemokine receptor internalization orthe delivery of compound in a manner that results in the misdirection ofthe migration of cells.

[0728] In addition to primates, such as humans, a variety of othermammals can be treated according to the method of the present invention.For instance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

[0729] Diseases or conditions of human or other species which can betreated with inhibitors of chemokine receptor function, include, but arenot limited to: inflammatory or allergic diseases and conditions,including respiratory allergic diseases such as asthma, allergicrhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., LoeffleR′s syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

[0730] Diseases or conditions of humans or other species which can betreated with promoters of chemokine receptor function, include, but arenot limited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases.

[0731] In addition, treatment of the aforementioned inflammatory,allergic and autoimmune diseases can also be contemplated for promotersof chemokine receptor function if one contemplates the delivery ofsufficient compound to cause the loss of receptor expression on cellsthrough the induction of chemokine receptor internalization or deliveryof compound in a manner that results in the misdirection of themigration of cells.

[0732] In another aspect, the instant invention may be used to evaluatethe putative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this-invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

[0733] Preferably, the compounds of the present invention are used totreat or prevent disorders selected from rheumatoid arthritis,osteoarthritis, septic shock, atherosclerosis, aneurism, fever,cardiovascular effects, haemodynamic shock, sepsis syndrom, postischemic reperfusion injury, malaria, Crohn's disease, inflammatorybowel diseases, mycobacterial infection, meningitis, psoriasis,congestive heart failure, fibrotic diseases, cachexia, graft rejection,autoimmune diseases, skin inflammatory diseases, multiple sclerosis,radiation damage, hyperoxic alveolar injury, HIV, HIV dementia,non-insulin dependent diabetes melitus, asthma, allergic rhinitis,atopic dermatitis, idiopathic pulmonary fibrosis, bullous pemphigoid,helminthic parasitic infections, allergic colitis, eczema,conjunctivitis, transplantation, familial eosinophilia, eosinophiliccellulitis, eosinophilic pneumonias, eosinophilic fasciitis,eosinophilic gastroenteritis, drug induced eosinophilia, cysticfibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin's disease, coloniccarcinoma, Felty's syndrome, sarcoidosis, uveitis, Alzheimer,Glomerulonephritis, and systemic lupus erythematosus.

[0734] More preferably, the compounds are used to treat or preventinflammatory disorders selected from from rheumatoid arthritis,osteoarthritis, atherosclerosis, aneurism, fever, cardiovasculareffects, Crohn's disease, inflammatory bowel diseases, psoriasis,congestive heart failure, multiple sclerosis, autoimmune diseases, skininflammatory diseases.

[0735] Even more preferably, the compounds are used to treat or preventinflammatory disorders selected from rheumatoid arthritis,osteoarthritis, atherosclerosis, Crohn's disease, inflammatory boweldiseases, and multiple sclerosis.

[0736] Combined therapy to prevent and treat inflammatory, infectiousand immunoregulatory disorders and diseases, including asthma andallergic diseases, as well as autoimmune pathologies such as rheumatoidarthritis and atherosclerosis, and those pathologies noted above isillustrated by the combination of the compounds of this invention andother compounds which are known for such utilities. For example, in thetreatment or prevention of inflammation, the present compounds may beused in conjunction with an anti-inflammatory or analgesic agent such asan opiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,a tumor necrosis factor inhibitor, an NMDA antagonist, an inhibitor ornitric oxide or an inhibitor of the synthesis of nitric oxide, anon-steroidal anti-inflammatory agent, a phosphodiesterase inhibitor, ora cytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

[0737] Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) integrin antagonists such as those for selectins, ICAMs and VLA-4;(b) steroids such as beclomethasone, methylprednisolone, betamethasone,prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressantssuch as cyclosporin, tacrolimus, rapamycin and other FK-506 typeimmunosuppressants; (d) antihistamines (H1-histamine antagonists) suchas bromopheniramine, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguamides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (l) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient.

[0738] Generally, an effective dose of each will be used. Thus, forexample, when a compound of the present invention is combined with anNSAID the weight ratio of the compound of the present invention to theNSAID will generally range from about 1000:1 to about 1:1000, preferablyabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

[0739] The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

[0740] Dosage and Formulation

[0741] The compounds of this invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

[0742] The dosage regimen for the compounds of the present inventionwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. A physician or veterinarian candetermine and prescribe the effective amount of the drug required toprevent, counter, or arrest the progress of the thromboembolic disorder.

[0743] By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

[0744] Compounds of this invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using transdermal skin patches. When administered in the form ofa transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen.

[0745] The compounds are typically administered in admixture withsuitable pharmaceutical diluents, excipients, or carriers (collectivelyreferred to herein as pharmaceutical carriers) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

[0746] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

[0747] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[0748] Compounds of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Dosage forms(pharmaceutical compositions) suitable for administration may containfrom about 1 milligram to about 100 milligrams of active ingredient perdosage unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

[0749] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet-from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

[0750] Liquid dosage forms for oral administration can contain coloringand flavoring to increase patient acceptance. In general, water, asuitable oil, saline, aqueous dextrose (glucose), and related sugarsolutions and glycols such as propylene glycol or polyethylene glycolsare suitable carriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0751] Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Representative useful pharmaceutical dosage-formsfor administration of the compounds of this invention can be illustratedas follows:

[0752] Capsules

[0753] A large number of unit capsules can be prepared by fillingstandard two-piece hard gelatin capsules each with 100 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

[0754] Soft Gelatin Capsules

[0755] A mixture of active ingredient in a digestable oil such assoybean oil, cottonseed oil or olive oil may be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules should be washed and dried.

[0756] Tablets

[0757] Tablets may be prepared by conventional procedures so that thedosage unit is 100 milligrams of active ingredient, 0.2 milligrams ofcolloidal silicon dioxide, 5 milligrams of magnesium stearate, 275milligrams of microcrystalline cellulose, 11 milligrams of starch and98.8 milligrams of lactose. Appropriate coatings may be applied toincrease palatability or delay absorption.

[0758] Injectable

[0759] A parenteral composition suitable for administration by injectionmay be prepared by stirring 1.5% by weight of active ingredient in 10%by volume propylene glycol and water. The solution should be madeisotonic with sodium chloride and sterilized.

[0760] Suspension

[0761] An aqueous suspension can be prepared for oral administration sothat each 5 mL contain 100 mg of finely divided active ingredient, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin. Where the compoundsof this invention are combined with other anticoagulant agents, forexample, a daily dosage may be about 0.1 to 100 milligrams of thecompound of Formula I and about 1 to 7.5 milligrams of the secondanticoagulant, per kilogram of patient body weight. For a tablet dosageform, the compounds of this invention generally may be present in anamount of about 5 to 10 milligrams per dosage unit, and the secondanti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination. Particularly when provided as asingle dosage unit, the potential exists for a chemical interactionbetween the combined active ingredients. For this reason, when thecompound of Formula I and a second therapeutic agent are combined in asingle dosage unit they are formulated such that although the activeingredients are combined in a single dosage unit, the physical contactbetween the active ingredients is minimized (that is, reduced). Forexample, one active ingredient may be enteric coated. By enteric coatingone of the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of theactive ingredients may also be coated with a material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a lowviscosity grade of hydroxypropylmethylcellulose (HPMC) or other appropriate materials as known in theart, in order to further separate the active components. The polymercoating serves to form an additional barrier to interaction with theother component.

[0762] These as well as other ways of minimizing contact between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time by the same manner, will be readily apparent tothose skilled in the art, once armed with the present disclosure.

[0763] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein thecycloalkyl group is saturated or partially unsaturated; or a heterocycleof 3 to 7 atoms wherein the heterocycle is saturated or partiallyunsaturated, the heterocycle containing a heteroatom selected from —O—,—S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the heterocycle optionallycontaining a —C(O)—; ring B being substituted with 0-2 R⁵; Z is selectedfrom a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO²—, and —SO₂NH—; R^(1a) andR^(1b) are independently selected from H, C₁₋₄ alkyl, C₁₋₄ cycloalkyl,CF₃, or alternatively, R^(1a) and R^(1b) are taken together to from ═O;R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a5-10 membered heteroaryl system containing 1-4 heteroatoms selected fromN, O, and S, substituted with 0-3 R⁶; R² is selected from a C₆₋₁₀ arylgroup substituted with 0-5 R⁷ and a 5-10 membered heteroaryl systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R⁷; R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),(CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),(CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);R^(4a), at each occurrence, is independently selected from H, methylsubstituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e),C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-4R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);R^(4b), at each occurrence, is selected from H, C₁₋₆ alkyl substitutedwith 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynylsubstituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(4e); R^(4c) is independently selected from —C(O)R^(4b),—C(O)OR^(4d), —C(O)NR^(4f)R^(4f), and (CH₂)rphenyl; R^(4d), at eachoccurrence, is selected from methyl, CF₃, C₁₋₆ alkyl substituted with0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynylsubstituted with 0-3 R^(4e), and a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(4e); R^(4e), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j),—C(O)NR^(4h)R^(4h), —OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h),—NR^(4h)C(O)OR^(4j), and (CH₂)_(r)phenyl; R^(4f), at each occurrence, isselected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(4h), ateach occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)-C₃₋₁₀ carbocyclic; R^(4i), ateach occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue; R^(4j), at eachoccurrence, is selected from CF₃, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, and a C₃₋₁₀ carbocyclic residue; R⁵, at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d),(CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b),(CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b),(CRR)_(r)OC(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)OR^(5d),(CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)H,(CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),(CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b),(CRR)_(r)NR^(5a)S(O)₂ NR^(5a)R^(5a), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5c), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(5c); R^(5a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(5g), C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(5e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(5e); R^(5b), at each occurrence, isselected from C₁₋₆ alkyl substituted with 0-3 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(5e), and a(CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(5e); R^(5c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b),(CH₂)_(r)C(O)NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)C(O)R^(5b),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(5b),(CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)_(p)R^(5b),(CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)₂NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)S(O)₂R^(5b), and (CH₂)_(r)phenyl substituted with 0-3R^(5e); R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5e); R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂) rSC₁₋₅ alkyl, (CH₂) rNR^(5f)R^(5f), and(CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(5g) is independently selected from—C(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R,at each occurrence, is selected from H, C₁₋₆ alkyl substituted withR^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(5e); R⁶, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(6a)R_(6a),(CR′R′)_(r)OH, (CR′R′) rO (CR′R′)_(r)R^(6d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O) (CR′R¹)_(r)R^(6b),(CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)C(O) (CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O) (CR′R′) rR^(6b),(CR′R′)_(r)OC(O)NR^(6a) (CR′R′) rR^(6d), (CR′R′) rNR^(6a)C (O)NR^(6a)(CR′R′) rR^(6d), (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R¹)_(r)R^(6d),(CR′R′)_(r)NR_(6f)C(O)O(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(═NR^(6f))NR^(6a)R_(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a), (CR′R′) rNR^(6f)S(O) 2 (CR′R′)rR^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenyl substituted with0-3 R^(6e); alternatively, two R⁶ on adjacent atoms on R¹ may join toform a cyclic acetal; R^(6a), at each occurrence, is selected from H,methyl substituted with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynylsubstituted with 0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(6e); R^(6b), at each occurrence, is selected from H, C₁₋₆alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5⁻⁶membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); R^(6d), at each occurrence, isselected from C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynylsubstituted with 0-2 R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with0-3 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(6e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R^(6f), at each occurrence,is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(6g)is independently selected from —C(O)R^(6b), —C(O)OR^(6d),—C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R⁷, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a),(CR′R′)_(r)OH, (CR′R′)_(r)°(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O) (CR′R¹)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O) (CR′R′) rR^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a), (CR′R′) rNR^(7a)C (O)NR^(7a)(CR′R′)_(r)R^(7a), (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)S(O)2(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3R′, C₂₋₈ alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenylsubstituted with 0-3 R^(7e); alternatively, two R⁷ on adjacent atoms onR² may join to form a cyclic acetal; R^(7a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(7g), C₂₋₆alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(7e); R^(7b), at each occurrence, isselected from C₁₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenylsubstituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a(CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a(CH₂)_(r)—S-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7e); R^(7d), at eachoccurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(7e),C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(7e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(7e); R^(7e), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, andphenyl; R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),—C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R′, at each occurrence, isselected from H, C₁₋₆ alkyl substituted with R^(6e), C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted withR^(6e); R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; R⁹ isselected from, H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and (CH₂)—R¹; R¹⁰ andR^(10a) are independently selected from H, and C₁₋₄alkyl substitutedwith 0-1 R^(10b), alternatively, R¹⁰ and R^(10a) can join to form a C₃₋₆cycloalkyl; R^(10b), at each occurrence, is independently selected from—OH, —SH, NR^(10c)R¹⁰c, —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹¹ isselected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b),(CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a),(CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b),(CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a),(CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-5 R^(11e), and a (CHR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e); R^(11a), at each occurrence, is independently selected fromH, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a(CH₂)_(r)—S-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e); R^(11b), ateach occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e); R^(11d), at each occurrence, is independently selected fromH, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆carbocyclic residue substituted with 0-3 R^(11e), and a (CH₂)_(r)—S-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e); R^(11e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and(CH₂)_(r)phenyl; R^(11f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹² is selected from H, C₁₋₄ alkyl,(CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d),(CHR)_(r)C(O)R^(12b), (CHR) rNR^(12a)R^(12a), (CHR) rC(O)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)OR^(12d),(CHR)_(q)NR^(12a)C(O)R^(12b), (CHR)_(q)NR^(12a)C(O)OR_(12d),(CHR)_(q)OC(O)NR^(12a)R^(12a), (CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e); R^(12a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-5 R^(12e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(12e); R^(12b), at each occurrence, is independently selectedfrom C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5⁻⁶membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e); R^(12d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl,C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R^(12e),and a (CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(12f)R^(l2f), and (CH₂)_(r)phenyl; R^(12f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹³, ateach occurrence, is independently selected from methyl, C₂₋₄ alkylsubstituted with 0-1 R^(13b); R^(13b) is selected from —OH, —SH,—NR_(13c)R^(13c), —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c); R^(13c) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; n is selected from 1and 2; m is selected from 0 and 1; p, at each occurrence, isindependently selected from 0, 1, and 2; q, at each occurrence, isindependently selected from 1, 2, 3, and 4; r, at each occurrence, isindependently selected from 0, 1, 2, 3, and 4; s, at each occurrence, isindependently selected from 0 and 1; and t, at each occurrence, isindependently selected from 2, 3, and
 4. 2. A compound claim 1, whereinring B is a cycloalkyl group of 3 to 8 carbon atoms wherein thecycloalkyl group is saturated or partially unsaturated; or a heterocycleof 3 to 7 atoms wherein the heterocycle is saturated or partiallyunsaturated, the heterocycle containing a heteroatom selected from —O—,—S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the heterocycle optionallycontaining a —C(O)—; ring B being substituted with 0-2 R⁵; Z is selectedfrom a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and —SO₂NH—; R^(1a) andR^(1b) are independently selected from H, C₁₋₄ alkyl, C₁₋₄ cycloalkyl,CF₃, or alternatively, R^(1a) and R^(1b) are taken together to from ═O;R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a5-10 membered heteroaryl system containing 1-4 heteroatoms selected fromN, O, and S, substituted with 0-3 R⁶; R² is selected from a C₆₋₁₀ arylgroup substituted with 0-5 R⁷ and a 5-10 membered heteroaryl systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R⁷; R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),(CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),(CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);R^(4a), at each occurrence, is independently selected from H, methylsubstituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e),C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with0-3 R^(4e), and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with0-4 R^(4e); R^(4b), at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e),C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R^(4e); R^(4c) is independentlyselected from —C(O)R^(4b), —C(O)OR_(4d), —C(O)NR^(4f)R^(4f), and(CH₂)_(r)phenyl; R^(4d), at each occurrence, is selected from methyl,CF₃, C₁₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substitutedwith 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4e); R^(4e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4i), —C(O)NR^(4h)R^(4h),—OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h), —NR^(4h)C(O)OR^(4j), and(CH₂)_(r)phenyl; R^(4f), at each occurrence, is selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(4h), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,and a (CH₂)_(r)-C₃₋₁₀ carbocyclic; R^(4i), at each occurrence, isselected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C³⁻⁸ alkynyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue; R^(4i), at each occurrence, isselected from CF₃, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀carbocyclic residue; R⁵, at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH,(CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),(CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b),(CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),(CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂ NR^(5a)R^(5a), C₁₋₆haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R⁵C; R^(5a),at each occurrence, is independently selected from H, methyl substitutedwith 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(5e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(5e); R^(5b), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-3 R^(5e),C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(5e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e);R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b),(CH₂)_(r)C(O)NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)C(O)R^(5b),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(5b),(CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)_(p)R^(5b),(CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)₂NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)S(O)₂R^(5b), and (CH₂)_(r)phenyl substituted with 0-3R^(5e); R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5e); R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(5f)R^(5f), and(CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(5g) is independently selected from—C(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R,at each occurrence, is selected from H, C₁₋₆ alkyl substituted withR^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(5e); R⁶, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR_(6a)R^(6a),(CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O) (CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6a)R^(6a),(CR′R¹)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O) (CR′R¹)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(6b),(CR′R′)_(r)OC(O)NR^(6a) (CR′R′) rR^(6d), (CR′R′) rNR^(6a)C(O)NR^(6a)(CR′R′) rR^(6d), (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R¹)_(r)R^(6d),(CR′R¹)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R¹)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R_(6a), (CR′R′) rNR^(6f)S(O)₂ (CR′l ′)rR^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenyl substituted with0-3 R^(6e); alternatively, two R⁶ on adjacent atoms on R¹ may join toform a cyclic acetal; R^(6a), at each occurrence, is selected from H,methyl substituted with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynylsubstituted with 0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(6e); R^(6b), at each occurrence, is selected from H, C₁₋₆alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5⁻⁶membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); R^(6d), at each occurrence, isselected from C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynylsubstituted with 0-2 R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with0-3 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(6e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R^(6f), at each occurrence,is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(6g)is independently selected from —C(O)R^(6b), —C(O)OR^(6d),—C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R⁷, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a),(CR′R′)_(r)OH, (CR′R′)_(r)°(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O) (CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O) (CR′R′) rR^(7b),(CR′R′)_(r)OC(O)NR^(7a) (CR′R′) rR^(7a), (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR₁ R′)_(r)R^(7a), (CR′R¹)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(7e); alternatively, two R⁷ onadjacent atoms on R² may join to form a cyclic acetal; R^(7a), at eachoccurrence, is independently selected from H, methyl substituted with0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenylsubstituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7e); R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(7e),C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(7e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl substitutedwith 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃,C₂₋₆ alkyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5⁻⁶ memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(7e); R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl, and phenyl; R^(7g) is independently selected from—C(O)R^(7b), —C(O)OR^(7d), —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R′,at each occurrence, is selected from H, C₁₋₆ alkyl substituted withR^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(6e); R⁸ is selected from H, C₁₋₄alkyl, and C₃₋₄ cycloalkyl; R⁹ is selected from, H, C₁₋₄ alkyl, C₃₋₄cycloalkyl, and (CH₂)—R¹; R¹⁰ and R^(10a) are independently selectedfrom H, and C₁₋₄alkyl substituted with 0-1 R^(10b), alternatively, R¹⁰and R^(10a) can join to form a C₃₋₆ cycloalkyl; R^(10b), at eachoccurrence, is independently selected from —OH, —SH, NR^(10c)R^(10c),—C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c); R^(10c) is selected from H,C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹¹ is selected from H, C₁₋₄ alkyl,(CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d),(CHR)_(r)C(O)R^(11b), (CHR)_(r)NR^(11a)R^(11a),(CHR)_(r)C(O)NR^(11a)R^(11a), (CHR)_(r)C(O)N-OR^(11d),(CHR)_(q)NR^(11a)C(O)R^(11b), (CHR)_(q)NR^(11a)C(O)OR^(11d),(CHR)_(q)OC(O)NR^(11a)R^(11a), (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e); R^(11a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5⁻⁶ membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11b), at each occurrence, is independently selectedfrom C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5⁻⁶membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e); R^(11d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl,C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R^(11e),and a (CH₂)_(r)-5⁻⁶ membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² isselected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),(CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a),(CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b),(CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),(CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-5 R^(12e), and a (CHR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e); R^(12a), at each occurrence, is independently selected fromH, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(12e); R^(12b), ateach occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e); R^(12d), at each occurrence, is independently selected fromH, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆carbocyclic residue substituted with 0-3 R^(12e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e); R^(12e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(l2f), and(CH₂)_(r)phenyl; R^(12f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹³, at each occurrence, is independentlyselected from methyl, C₂₋₄ alkyl substituted with 0-1 R^(13b); R^(13b)is selected from —OH, —SH, —NR_(13c)R^(13c), —C(O)NR^(13c)R^(13c), and—NHC(O)R^(13c); R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆cycloalkyl; n is selected from 1 and 2; m is selected from 0 and 1; p,at each occurrence, is independently selected from 0, 1, and 2; q, ateach occurrence, is independently selected from 1, 2, 3, and 4; r, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; s, ateach occurrence, is independently selected from 0 and 1; and t, at eachoccurrence, is independently selected from 2, 3, and
 4. 3. The compoundof claim 2, wherein: R¹⁰ and R^(10a) are H; m is 0; n is 1; and s is 0.4. The compound of claim 3, wherein: ring B is selected from

ring B being optionally substituted with 0-1 R⁵; and R¹¹ and R¹² are H.5. The compound of claim 4, wherein: R⁵, at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d),(CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b),(CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b),(CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)OC(O)NR^(5a)R^(5a),(CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), CRR(CRR)_(r)NR^(5a)C(O)H,(CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),(CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆haloalkyl; R^(5a), at each occurrence, is independently selected from H,methyl, C₁₋₆ alkyl substituted with 0-2 R^(5e) wherein the alkyl isselected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, C₃alkenyl substituted with 0-1 R^(5e), wherein the alkenyl is selectedfrom allyl, C₃ alkynyl substituted with 0-1 R^(5e) wherein the alkynylis selected from propynyl, and a (CH₂)_(r)—C₃₋₄ carbocyclic residuesubstituted with 0-5 R^(5e), wherein the carbocyclic residue is selectedfrom cyclopropyl, and cyclobutyl; R^(5b), at each occurrence, isselected from C₁₋₆ alkyl substituted with 0-2 R^(5e), wherein the alkylis selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,pentyl, and hexyl, a (CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with0-2 R^(5e), wherein the carbocyclic residue is selected fromcyclopropyl, and cyclobutyl; and R^(5d), at each occurrence, is selectedfrom methyl, CF₃, C₂₋₆ alkyl substituted with 0-2 R^(5e), wherein thealkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,pentyl, and hexyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(5e).
 6. The compound of claim 5,wherein: R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)oR^(4d), (CRR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b),(CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a),(CRR)_(r)NR^(4a)S(O)₂R^(4b); R, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(6e); R⁵, at eachoccurrence, is independently selected from H, methyl, ethyl, propyl,i-propyl, butyl, i-butyl, allyl, propynyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(5d), (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a),(CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)OC(O)NR^(5a)R^(5a),(CH₂)_(r)NR^(5a)C(O)OR^(5d), (CH₂)_(r)NR^(5a)C(O)R^(5b),(CH₂)_(r)C(O)OR^(5b), (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)NR^(5a)S(O)₂R^(5b),and C₁₋₆ haloalkyl; R^(5a), at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,pentyl, hexyl, cyclopropyl, and cyclobutyl; and r, at each occurrence,is selected from 0, 1, and
 2. 7. The compound of claim 6, wherein: R¹ isselected from phenyl substituted with 0-2 R⁶, naphthyl substituted with0-2R⁶, and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁶ wherein theheteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,thiazolyl, thienyl, and tetrazolyl; R² is selected from phenylsubstituted with 0-2 R⁷, and a 5-10 membered heteroaryl systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R⁷ wherein the heteroaryl is selected from indolyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl,isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl; R⁴ is selected from H,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)oR^(4d), (CRR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b),(CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a),(CRR)_(r)NR^(4a)S(O)₂R^(4b); R^(4a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(4c), C₂₋₆alkyl substituted with 0-3 R^(4e) wherein C₂₋₆ is selected from ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl and hexyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-4 R^(4e) whereinthe carbocyclic residue is selected from cyclopropyl, cyclohexyl, andphenyl; R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; R^(4d) is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and cyclopropyl; R⁸ is selected from H, methyl, ethyl, propyl, i-propyl,and cyclopropyl; and R⁹ is selected from H, methyl, ethyl, propyl,i-propyl, and cyclopropyl, and CH₂—R¹.
 8. The compound of claim 7,wherein: R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)OH, (CRR)_(r)O(CRR)_(r)R^(6d),(CRR)_(r)SH, (CRR)_(r)C(O)H, (CRR)_(r)S(CRR)_(r)R^(6d), (CRR)_(r)C(O)OH,(CRR)_(r)C(O) (CRR)_(r)R^(6b), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)NR^(6f)C(O) (CRR)_(r)R^(6b), (CRR)_(r)C(O)O(CRR)_(r)R^(6d),(CRR)_(r)NR^(6a)C(O)NR^(6a)R^(6a), (CRR)_(r)NR^(6a)C(S)NR^(6a)R^(6a),(CRR)_(r)OC(O)(CRR)_(r)R^(6b), (CRR)_(r)S(O)_(p)(CRR)_(r)R^(6b),(CRR)_(r)S(O)₂NR^(6a)R^(6a), (CRR)_(r)NR^(6f)S(O)₂(CRR)_(r)R^(6b),(CRR)_(r)NR^(6f)S(O)₂ NR^(6a)R^(6a), C₁₋₆ haloalkyl, and (CRR)_(r)phenylsubstituted with 0-3 R^(6e); R^(6a), at each occurrence, isindependently selected from H, methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, hexyl, cyclopropyl and phenyl; R^(6b), at eachoccurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; R^(6d), ateach occurrence, is selected from methyl, CF₃, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; R^(6e),at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R^(6f), at each occurrence,is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; R⁷ is selected frommethyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl,pentyl, hexyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CRR)_(r)NR^(7a)R^(7a), (CRR)_(r)OH, (CRR)_(r)O(CH)_(r)R^(7d),(CRR)_(r)SH, (CRR)_(r)C(O)H, (CRR)_(r)S(CRR)_(r)R^(7d), (CRR)_(r)C(O)OH,(CRR)_(r)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)NR^(7a)R^(7a),(CRR)_(r)NR^(7f)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)O(CRR)_(r)R^(7d),(CRR)_(r)OC(O)(CRR)_(r)R^(7b), (CRR)_(r)NR^(7a)C(O)NR^(7a)R^(7a),(CRR)_(r)NR^(7a)C(O)O(CRR)_(r)R^(7d), (CRR)_(r)S(O)_(p)(CRR)_(r)R^(7b),(CRR)_(r)S(O)₂NR^(7a)R^(7a), (CRR)_(r)NR^(7f)S(O)₂(CRR)_(r)R^(7b), C₁₋₆haloalkyl, and (CRR)_(r)phenyl substituted with 0-3 R^(7e); R^(7a), ateach occurrence, is selected from H, methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, hexyl prop-2-enyl, 2-methyl-2-propenyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH₂-cyclopropyl, andbenzyl; R^(7b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,cyclopentyl, CH₂-cyclopentyl, cyclohexyl, CH₂-cyclohexyl, CF₃,pyrrolidinyl, morpholinyl, and azetidinyl; R^(7d), at each occurrence,is selected from methyl, CF₃, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, hexyl, and cyclopropyl; R^(7e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,cyclopropyl, and phenyl; and r is 0 or
 1. 9. The compound of claim 8,wherein R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂, NR^(7a)R^(7a),NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, OCF3,C(O)R^(7b), NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),


10. Th e compoun d of claim 9, wherein ring B is selected from

Z is —C(O)—; R^(1a) and R^(1b) are selected from H and methyl, oralternatively, R^(1a) and R^(1b) are taken together to form ═O; R¹ isselected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶ wherein thearyl group is selected from phenyl and naphthyl, and a 5-10 memberedheteroaryl system containing 1-4 heteroatoms selected from N and O,substituted with 0-3 R⁶ wherein the heteroaryl system is selected fromfuryl, indolyl, and benzotriazolyl; R² is phenyl substituted with 0-1R⁷; R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,1-butyl, t-butyl, pentyl, hexyl, and (CH₂)_(r) C(O)R^(4b); R⁶ isselected from methyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I, NO₂,CN, O(CH₂)_(r)R^(6d), C(O)H, SR_(6d), NR^(6a)R^(6a), OC(O)R^(6b), S(O)pR_(6b), (CHR′)_(r)S(O)₂NR^(6a)R^(6a), CF₃; R^(6a) is H methyl, orethyl; R^(6b) is H or methyl; R^(6d) is methyl, phenyl, CF₃, and(CH₂)-phenyl; R⁹ is selected from H, methyl, and (CH₂)—R¹; and r is 0or
 1. 11. The compound of claim 1, wherein the compound is selectedfrom: N-[2-[[(1-S,2S)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2,4,6-Trimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(4-Benzyloxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2,4-Difluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2-Chloro-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2-Trifluoromethyl-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2,4-Dichlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2-Fluoro-6-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(2-Chloro-5-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[(2,4-Dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-2-[(4-Chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Nitrophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Isopropylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Trifluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Trifluoromethoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Phenoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(2-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(3-Indolyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[1-(4-Chlorophenyl)ethyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[Bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[(4-Chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[(4-(Methylthio)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[(4-(Methylsulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[(4-Iodobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[(4-(Aminosulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[[(4-Chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-2-[[(4-Methylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Methylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Fluorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[Benzoylamino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Bromobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Phenoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Trifluoromethylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(5-Benzotriazolecarbonyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Iodobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Cyanobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Trifluoromethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Formylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Carbomethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Nitrobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Methoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Methylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Methylsulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Aminosulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Isopropylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Phenylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-(N,N-diethylsulfamoyl)benzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[(4-Trifluoromethylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(3,4-Dimethylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(cis)-2-[[(4-Methylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodobenzamide;2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-chlorobenzamide;N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-chlorobenzamide;N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-trifluoromethoxybenzamide;Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamidetrifluoroacetate;4-(Aminosulfonyl)-N-((cis)-2-{[({[2-(trifluoromethyl)anilino]carbonyl}amino)acetyl]aminoIcyclohexyl)benzamide;4-(Aminosulfonyl)-N-{(cis)-2-[({[(3-chlorophenyl)sulfonyl]amino}acetyl)amino]cyclohexyl}benzamide; Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;Methyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;Tert-butylN-Methyl-2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;2-(Benzylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-bromobenzamide; Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethoxy)phenylcarbamate;2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethoxybenzamide;2-(Allylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(cyclopropylmethylene)amino-N-[2-[[(cis)-2-[[4-*(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(butyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((2-methyl-2-propyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(acetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide;2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide;2-(Trifluoroacetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide;2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-nitrobenzamide; Iso-propyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;Tert butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3,5-dinitrobenzamide;2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Cyclopentylmethylenecarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Methylsulfonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((2-Methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Ethylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Allylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Iso-butylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Cyclopentylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Tert-butoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Iso-propoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Ethoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Pyrrolidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Morpholinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-((Azetidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide;2-{[1-Pyrrolidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methoxy)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;[2-({[5-benzyloxycarbonylamino-2-(4-methylthio-benzoylamino)cyclohexylcarbamoyl]-methyl}carbamoyl)-4-trifluoromethylphenyl]carbamic acid tert-butyl ester;{4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;(4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid benzyl ester;1-(4-Methanesulfonylbenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl-4-aminocyclohexane;1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)cyclohexane;1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(3-methylureido)cyclohexane;1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-aminocyclohexane;1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-(2-propylamino)cyclohexane;1-(4-Methylthio-benzoylamino)-2-[2-(2-Amino-5-trifluoromethyl-benzoylamino)-acetylamino]-4-aminocyclohexane;4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)-cyclohexane;1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-5-aminocyclohexane;2-Amino-N-({2-[(4-methylthiophenylamino)methyl]cyclohexylcarbamoyl}-methyl)-5-(trifluoromethyl)benzamide;2-Isopropylamino-N-{[(cis)₂-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide;2-(3-Isopropylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide;2-(3-Morpholinylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide;2-Amino-N-({2-(cis)-[3-(4-methylthiophenyl)ureido]cyclohexylcarbamoyl}methyl)-5-trifluoromethylbenzamide;{2-[({2-(Cis)-[3-(4-methanesulfonylphenyl)ureido]cyclohexylcarbamoyl}methyl) carbamoyl]-4-trifluoromethylphenyl} carbamic acid tert-butyl ester;2-amino-N-{2-[((3S,4R)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-Amino-N-{2-[((3R,4S)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;2-Amino-N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-Amino-N-{2-[((cis)-4-{[4-ethylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{bis[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-(Pyrrolidinylcarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-(Methylaminocarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-aminosulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-methylsulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;2-Amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;N-{2-[((cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;N-{[4-Dimethylamino-2-(4-methylsulfanyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate;N-{[2-(4-Chloro-benzylamino)-4-dimethylamino-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate;N-{[4-Dimethylamino-2-(4-methoxy-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate; andN-{[4-Dimethylamino-2-(4-methyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate.
 12. A pharmaceutical composition, comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim
 1. 13. A method for modulation ofchemokine or chemokine receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim
 1. 14. A method for modulation of MCP-1, MCP-2, MCP-3 andMCP-4, and MCP-5 activity that is mediated by the CCR₂ receptorcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 15. A method for modulationof MCP-1 activity comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim
 1. 16. Amethod for treating or preventing disorders, comprising administering toa patient in need thereof a therapeutically effective amount of acompound of claim 1, said disorders being selected from osteoarthritis,aneurism, fever, cardiovascular effects, Crohn's disease, congestiveheart failure, autoimmune diseases, HIV-infection, HIV-associateddementia, psoriasis, idiopathic pulmonary fibrosis, transplantarteriosclerosis, physically- or chemically-induced brain trauma,inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 17. Themethod for treating or preventing disorders, of claim 16, wherein saiddisorders being selected from psoriasis, idiopathic pulmonary fibrosis,transplant arteriosclerosis, physically- or chemically-induced braintrauma, inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 18. Themethod for treating or preventing disorders, of claim 17, wherein saiddisorders being selected from alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 19. Themethod for treating or preventing disorders, of claim 18, wherein saiddisorders being selected from asthma, multiple sclerosis,artherosclerosis, and rheumatoid arthritis.
 20. A method for treating orpreventing rheumatoid arthritis, comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim
 1. 21. A method for treating or preventing multiple sclerosis,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 22. A method for treating orpreventing atherosclerosis, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound ofclaim
 1. 23. A method for treating or preventing asthma, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim
 1. 24. A method for treating or preventinginflammatory diseases, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim
 1. 25.A method for modulation of CCR₂ activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1.